ACQUIRED HEMOLYTIC ANEMIA*
A. S. W I E N E R , M . D . , A. A. SAMWICK, M . D . , M. M O R R I S O N , M . D . ,
AND L. LOEWE, M . D .
From the Department of Laboratories, Division of Transfusion
and Hematology,
Medical Service, The Jewish Hospital of Brooklyn, Brooklyn, N. Y.
and the
The purpose of this paper is to describe three unusual examples of acquired
hemolytic anemia, with special reference to the role of autoantibodies in the
pathogenesis of the disease.
Donath and Landsteiner,10 as early as 1902, were the first workers to demonstrate the importance of red cell autoantibodies as a cause of hemolysis in vivo.
They demonstrated that the serum of patients with paroxysmal hemoglobinuria
contained abnormal antibodies, and devised the cold autohemolysis test for the
diagnosis of this condition. In fact, Landsteiner and Donath's work may be considered to mark the beginning of "immuiiohematology," which has become so
important in recen.t years.
The existence in some individuals of a predisposition to anemia because of
a congenital and hereditary anomaly of the red blood cells had been recognized
previously. As early as 1871, A'iinlair and Masius28 published an accurate description of familial hemolytic icterus (later, the name "familial spherocytosis"
was suggested,22 and more recently the term "heredity spherocytosis" was recommended by the Committee on Nomenclature f). Chauffard,2 in 1907, with the aid
of the fragility test introduced by A^aquez and Ribie'rre,29 demonstrated decreased
resistance of red blood cells to hypotonic saline in this disorder. Previously,
Hayem' 3 had encountered patients having chronic icterus and splenomegaly,
appearing relatively late in life and without any family history of the disorder.
AVidal, Abrami and Brul631 pointed out that these patients had acquired hemolytic anemia, and emphasized the distinction between the hereditary and acquired
forms of hemolytic anemia. The latter workers,31 as well as Chauffard and
Alncent,4 and Chauffard and Troisier,3 reported that the blood of patients with
acquired hemolytic anemia constantly exhibited autoagglutination, and stressed
the diagnostic importance of this finding. However, their work was apparently
overlooked for a number of years and, until relatively recently, many hematologists (see Dawson9) believed that all instances of idiopathic hemolytic anemia,
even those with late onset, belonged to the hereditary spherocytic type.
In 1925, Lederer17 again called attention to the existence of rare examples of
acquired hemolytic anemia of unknown etiology. The anemia described by
Lederer, however, appears to be a special clinical entity with an acute onset
suggesting an infectious origin and, as a rule, having a good prognosis. More
* Aided by a grant from the Jacques Loewe Research Foundation, New York, New York.
Received for publication, October 26, 1951.
f Third, fourth and fifth reports of the committee for clarification of the nomenclature
of cells and diseases of the blood and blood forming organs. Am. J. Clin. P a t h . , 20: 562579, 1950.
301
302
W I E N E R ET
Ah.
recently, patients with hemolytic anemia resembling that described by Lederer
have been found to have no autoantibodies, 33 indicating that they belong to a
different group from those studied by Widal and Chauffard. The occurrence of
hemolytic anemia of infectious origin in man, aside from anemia caused by sepsis,
malaria or Bartonella infection, does not seem improbable in view of the demonstration of hemolytic anemia of virus etiology in horses, which is transmissible to
man,24 as well as the recent work on the adsorption of virus onto red cells.
A new era was opened in 1938 by the studies of Dameshek and Schwartz s on
hemolytic anemias. They injected guinea-pig blood into rabbits in order to produce anti-guinea-pig hemolytic serum, and then studied the effects of injections
of this immune serum into the blood stream of guinea pigs. Depending on the
dosage, there resulted either a fulminating, fatal hemolytic anemia with frank'
hemoglobinuria, or an acute or subacute hemolytic anemia characterized by
spherocytosis, increased red-cell fragility and reticulocytosis. Based on the
similarity of the clinical pictures of the experimental disease and hemolytic
anemia in man, Dameshek and Schwartz concluded that circulating antibodies
were the cause of many hemolytic anemias in man, both of the congenital and
acquired varieties. The situation was further clarified by the transfusion experiments of Loutit and Mollison19 on patients with hemolytic disorders. By studies
on the survival of the transfused red cells of patients with hemolytic disorders in
normal recipients, and of the blood from normal persons transfused to such
patients, they demonstrated that the defect in the hereditary form of hemolytic
anemia is in the red cells, while in the acquired type there is a hemolytic agent
present in the patient's plasma.
When considering the role of autoantibodies* in acquired hemolytic anemia,
one must take into account the fact that there are two principal forms of such
autoantibodies. One form occurs naturally in the serum of all normal persons.15
These antibodies are of low titer and usually cannot be demonstrated except in
tests carried out at low temperatures 16 or by employing specific sensitive antigens
such as enzyme-treated red blood cells. 26 ' 41 Thus, every normal person's serum
will clump his own red cells after the latter have been treated with enzymes such
as trypsin and papain, especially when the tests are carried out at low temperatures. Wiener39 has suggested that these normal antibodies are of heterogenetic
origin, due to latent or manifest infections with microorganisms possessing antigens chemically related to structures present in human red blood cells. In support
of this hypothesis it may be pointed out that the titer of these cold autoantibodies
may be strikingly increased in certain specific infections, such as atypical pneumonia,' 4 ' 26 mumps18 and trypanosomiasis.43
Normally no person's serum will clump his own red cells at body temperature.
When the cold autoantibodies are markedly increased in titer, however, the
reactions may also take place at body temperature and occasionally a hemolytic
* Autoantibodies have the ability to react not only with an individual's own red cells
but also with the red cells of all other human subjects. Therefore, autoantibodies are
specific for antigens present in every human blood, in contrast to antigens such as A, B,
M, N and Rh, which are type-specific.
ACQUIRED HEMOLYTIC ANEMIA
303
anemia results.1 Moreover, a second type of autoantibody exists, which acts preferentially at body temperatures. 34 This type of autoantibody does not occur
normally and is apparently the result of true autosensitization, in contrast to the
cold autoantibodies. Luckily, such exceptions to Ehrlich's principle, "horror
autotoxicus," are rare, but when they occur may lead to a hemolytic anemia.
The distinction between the two kinds of autoantibodies may be clarified with
the aid of Ehrlich's lock-and-key analogy. The autoantibodies which act preferentially at body temperature may be considered to be the specific key, while the
cold autoantibodies may be compared to a skeleton key. The situation is further
complicated by the fact that each form of autoantibody (cold or warm) itself may
occur in at least two forms. This is a property of antibodies of all specificities,
the recognition of which was a result of the observations on Rh sensitization.37
One form of the antibodies, whether Rh or autoantibodies or other antibody, is
the so-called "bivalent" antibody or agglutinating antibody which clumps red
cells in saline medium. The other form, the "univalent" antibody, otherwise
known as blocking antibody, glutinin and incomplete antibody, clumps cells
only in colloid media, such as plasma, albumin and acacia. The warm autoantibodies which cause acquired hemolytic anemia occur, as a rule, in the univalent
form23'36 though some instances have been encountered with such antibodies
active in saline medium. 27,34 Accordingly their demonstration, in most cases,
had to await the development of special technics for demonstrating univalent
Rh antibodies, i.e., the conglutination test,36 the antiglobulin test (Moreschi,20
Coombs el al.b), and employment of enzyme-treated cells.21 • 2 6 , 3 0 , 4 0 In the original test for autoantibodies utilized by Widal, Abrami and Brule, ten drops of
the patient's serum were mixed with one drop of his own washed red cells on an
open slide. Thus, these early workers were unwittingly adopting conditions favorable to conglutination, which accounts for the success they had with their test.
From the therapeutic standpoint, a recent development has been the suggestion to administer ACTH and Cortisone in the treatment of acquired hemolytic
anemia.8
In this paper the case histories will illustrate the contrasting immunologic
mechanisms giving rise to acquired hemolytic anemia, and the variable course
and response to therapy of the different forms of the disease.
Case 1
Mrs. 13., a 47-year-old white housewife was seen on September S, 1950, because of weakness and refractory anemia. T h e present illness began one year previously with swelling
of the lymph nodes of the neck. Despite the absence of abnormal cells in the peripheral
blood, u hematologist made a diagnosis of chronic lymphatic leukemia, based on the results
of bone marrow and lymph node aspirations. X-ray therapy was given and the swelling
disappeared. A second hematologist saw her about six months later and reported a "negative Coombs t e s t " . She was then hospitalized because of weakness and faintness and was
given numerous blood transfusions, many of which were followed by severe reactions, a t
times with hemoglobinuria.
/
On September S the blood hemoglobin was 6.0 C m . per 100 ml., and the red blood count,
2.05 million per cu. mm. The white count was 20,150 per cu. mm. and the differential count
showed polymorphonuclears 33, large lymphocytes 5, small lymphocytes 50, and mono-
304
WIENER ET AL.
cytes 2 per cent. T h e patient was found to belong to group 0 , type M, type RhiRhi. T h e
icterus index of her serum was 16 units. Tests for free antibodies in the serum were negative not only in the agglutination and conglutination tests, but also with enzyme-treated
test cells. However, the p a t i e n t ' s cells were coated since they clumped when suspended
in albumin-plasma mixture and in tests with antiglobulin serum.
Since the patient's son also belonged to group 0 , type M, type RhiRhi, and his blood was
compatible in in vitro cross-matching tests, it was decided to administer his blood for transfusion. A biologic test 35 with 50 ml. of his blood was negative, and then500 ml. of his citrilled
blood was given during an hour. The patient felt well and was able to leave the office, b u t
16 hours later, a t home, she had a chill and her temperature rose. A blood count done the
next day showed the hemoglobin concentration to be 6.6 Gm. per 100 ml., the red blood
count 2.3 million and the white blood count 11,930 per cu. mm., the reticulocyte count 20
. per cent, and 4 nucleated red blood cells per 100 white blood cells. The icterus index again
was 16 units. When seen on September 15th, one week after the transfusion, the patient
was very weak, and had a hemoglobin level of only 3.0 Gm. She was admitted to the hospital
for t r e a t m e n t .
On the day of admission, following a negative biologic test, she was given 1000 ml. of
group O, type RhiRhi citrated blood, and this was followed by a mild chill and fever. The
next morning she felt well. However, by September 18 the patient again felt weak and the
hemoglobin concentration again was only 3.0 Gm. per 100 ml., while the red blood count
was 800,000 per cu. mm. After a negative biologic test, she was given 500 ml. of citrated blood
with no reaction, b u t after a second 500 ml. was given the temperature rose to 106.6 F . At
the same time, therapy with ACTH was s t a r t e d ; 50 mg. was given intramuscularly. Following the transfusion reaction the serum icterus rose to 3S.5 units, and the urine was dark
and yielded a one-plus guaiac reaction. There was no oliguria or anuria. The following
morning the patient was given another close of A C T H , and because of her desperate condition another transfusion of packed red blood cells was undertaken. Again the patient
sustained a severe reaction. She became dyspneic, orthopneic and comatose and developed
severe ventricular tachycardia and rales throughout both lung fields. She rallied following
medical t r e a t m e n t and the pulmonary edema subsided. However, she still had an urgent
need for blood, but since she could not tolerate transfusions of blood, these were withheld
and the p a t i e n t expired. Permission for postmortem examination was denied.
Case 2
On September 26, 1950, we were requested to see a white, obese female patient, 16 years
of age, because of a transfusion reaction with hemolysis. This patient was being treated
for purpura and anemia, and had recently been transferred from another hospital.
In the past history there was little of importance except t h a t from the age of six years,
the patient began to put on excessive weight and a t the age of 11 years was very obese.
At another hospital a diagnosis of hypothyroidism was made despite a basal metabolic
rate of only minus 1 per cent, and the patient was given thyroid and Dexedrine.* Recently
the patient had had an attack of pleurisy and was treated with a sulfa drug. She denied
ever having taken any other medication. Her menses began a t the age of 11 years.
In May 1950, the patient began to have an aching feeling in both calves. At the same
time, petechiae appeared on the legs and in both antecubital fossae, and she began to have
profuse menorrhagia. A blood count showed a hemoglobin level of 7.8 Gm. T r e a t m e n t consisted of liver, iron and a diet. The persistence of purpura and menorrhagia led to admittance
to another hospital. The patient had a severe anemia (hemoglobin concentration of 6.0 Gm.
per 100 ml. and red cell count of 2.5 million per cu. mm.) and was given 12 blood transfusions.
The platelet count was reported as normal on admission, but dropped within a few days t o .
about 50,000.per cu. mm., where it remained. A continuous reticulocytosis was noticed
* D e x t r o a m p h e t a m i n e sulfate, manufactured by Smith, Kline & French, Philadelphia,
Pa.
ACQUIRED HEMOLYTIC ANEMIA
305
(2 to 6 per cent) throughout the hospital stay. Material aspirated from the sternal bone
marrow showed hypoplasia of all the bone marrow elements.
On admission to this hospital (Medical Service of D r . Leo Locwe), the patient was noted
to have severe pallor and slight jaundice with petcchiae and purpuric spots on the arms,
legs and trunk, and also petcchiae on the mucous membranes of the mouth. Because of the
anemia the patient was transfused with 500 ml. of citratcd blood with no reaction, b u t a
second blood transfusion of 1000 ml. gave rise to the reaction we investigated.
T h e blood of the patient was found to be of group A, subgroup Ai. The patient was Rhopositivc but the exact Rh-Hr and M-N type could not be determined a t first, because the
p a t i e n t ' s blood contained a large amount of surviving donor cells. The icterus index of the
pretransfusion sample was 16 units, while the icterus index of the posttransfusion sample
was 20 units, indicating t h a t the transfusion had caused accelerated hemolysis. Tests for
coating of the patient's cells by autoantibodies were positive by the antiglobulin method,
but negative by the conglutination method. Tests for free autoantibodies were negative
by the agglutination and conglutination methods, b u t distinct clumping occurred with
enzyme-treated cells. It is clear, therefore, t h a t the patient was autosensitizod and this,
no doubt, was the cause of the severe anemia, and seemingly also the cause of the transFirst Admission
io Hospital
Second Admission
Third Admission
F I G . 1. Summary of hematologic findings and therapy in Case 2
fusion reaction. An unusual feature was the marked thrombocytopenia. This finding appears
to support the concept of one of the authors 3 8 t h a t the syndrome designated as thrombotic
thrombocytopenic purpura is merely one of the manifold manifestations of autohemolytic
disease. They, furthermore, corroborate the observations of Evans and his coworkers, 1 1 ' '?
pointing out the relationship between acquired hemolytic anemia and certain cases of
idiopathic thrombocytopenic purpura. According to the hypothesis advanced by E v a n s and
associates, in addition to red cell autoantibodies, antibodies may be formed reacting with
the platelets or even with the white cells, thus accounting for the thrombocytopenia and
leukopenia. Our patient, however, never exhibited a leukopenia throughout her stay in
the hospital.
Despite the patient's critical condition, with severe anemia and low blood pressure
bordering on shock so t h a t she became dyspneic on the slightest exertion even while lying
. in bed, our untoward experience in Case 1 caused us to withhold blood transfusion therapy.
We decided instead to initiate ACTH therapy and to maintain the p a t i e n t ' s blood pressure
with plasma transfusions. Accordingly, the patient was given 25 mg. of ACTH intramuscularly every 6 hours and 500 ml. of plasma daily (cf. Fig. 1). The blood pressure rose while
the hematocrit value, hemoglobin concentration and red cell count gradually fell. Daily
306
WIENER
ET
AL.
tests revealed a progressive drop in icterus index, and tests for autoantibodies with enzyme-treated cells gave progressively weaker clumping until (see Table 1) one week later,
when the reactions were completely negative.
In view of the favorable serologic response to therapy, it was decided to t r y transfusions
of whole blood again. All this time the patient continued to ooze blood from the vagina
and from every puncture wound, so t h a t the nurses remarked t h a t the patient probably
lost as much as an ounce of blood with each injection. After a negative biologic test a transfusion of 1000 ml. of whole blood was given with no reaction. Despite the absence of reaction and continued fall of the icterus index to 2 units, the red blood count, failed to rise.
This was apparently the result of loss of blood by bleeding. The dosage of ACTH was reduced and blood transfusion therapy continued as shown in Figure 1. The blood count
and hematocrit value finally rose to satisfactory levels. There was no recurrence of jaundice,
but purpura and thrombocytopenia, persisted (cf. Fig. 1). Bone marrow aspiration revealed
an active marrow with normal distribution of all the marrow elements.
TABLE 1
T E S T S F O K AUTOANTIBODIES D U R I N G F I R S T C O U R S E OF A C T H T H E R A P Y
( C A S E 2)
TESTS FOR COATING OF CELLS BY
DATE OF TEST, 1950
Sept. 27:
Pretransfusion
Posttransfusion
Sept. 29
Sept. 30
Oct. 1
Oct. 2
Oct. 3
Oct. 4
Oct. 5
Conglutination
(Albumin-Plasma
Mixture)
Antiglobulin
Method
±
+
—
-
—
—
—
—
-
±
±
±
TESTS FOR F R E E AUTOANTIBODIES BY
Conglutination
(Albumin-Plasma)
—
—
—
—
—
-
Enzyme-Treated
Cells*
++
++
++
+
—
—
-
ICTERUS
INDEX,
UNITS
16
20
10
S
s
s
4
4
4
* Enzyme employed was papain.
By this time the patient had been under our t r e a t m e n t for about five weeks. She was kept
under observation for two weeks more. F u r t h e r transfusions of whole blood were given,
and again the patient had hemolytic reactions and the icterus index rose to 9 units. In view
of the failure of the purpura to improve after A C T H therapy (admittedly in relatively
small dosage), a splenectomy was undertaken on November 2S, 1950. At the operation
considerable bleeding occurred and it was necessary to resort to packing a t the operative
site to control hemorrhage. T o counteract the bleeding, additional transfusions of whole
eitrated blood were given and the patient again had a mild hemolytic reaction. A restudy
of the p a t i e n t ' s blood (after all donors' cells had been eliminated) showed her to belong to
group A!, type M N , typo Rh 2 rh, and to be Kell-negative, and t h a t her serum contained not
only weak autoantibodies, b u t also antibodies against the• Kell (or Si) factor 6 , n with a
titer* of 12S units by the antiglobulin and conglutination technics. Thereafter, only Kellnegative donors served for transfusing the patient, and the p a t i e n t ' s blood count then rose.
T h e hemoglobin concentration increased to 12.S Gm. per 100 ml. and the red cell count
* The titer of a serum in units is the reciprocal of the highest dilution giving a distinct
(one-plus) reaction.
ACQUIRED HEMOLYTIC ANEMIA
307
rose to 4.1 million per cu. mm. on J a n u a r y 5, 1951 (cf. Fig. 1). The patient was discharged
three clays later. At the time of discharge the platelet count was still low and the bleeding
time still markedly prolonged. It is necessary to point out t h a t the immediate results of the
splenectomy were disappointing. There was only a slight temporary increase in the platelet
count, the bleeding time remained prolonged, and the packing a t the operative site posed
a problem. Attempts to remove the packing caused severe bleeding, and this was only accomplished by removing small portions a t a time over a period of two weeks. Hemorrhage
during this time was counteracted by transfusions.
At home the patient felt well for one week and then had headaches and nosebleeds for
a few days. She then had chills and fever, passed dark urine, and complained of nausea and
abdominal cramps. She was readmitted to the hospital with a temperature of 102 F . , a
pulse rate of 130 and a respiratory rate of 20 per minute. T h e hemoglobin concentration
was 8.1 Gm., the red blood cell count was 2.4 million, and the platelets were markedly reduced. Tests for autoantibodies were again positive, the titer being 6 units against enzymetreated cells. These tests, like the previous ones, were carried out at 37 C. We were not
dealing merely with cold autoantibodies because the titer of the antibodies a t refrigerator
temperature was also about 6 units, as shown in Table 2. T h e anti-Kell antibodies were
still demonstrable, with a titer of 64 units to 128 units by the antiglobulin and conglutination methods. Tests for coating of the patient's cells were negative by the conglutination
method but positive by the antiglobulin method. The icterus index was 13 units. Our conclusion was t h a t the patient had had another hemolytic crisis caused by an exacerbation
of the autosensitization. I t was decided to treat the patient again with ACTH, while withholding transfusion therapy.
The patient was again given 25 mg. of A C T H intramuscularly every six hours and while
this was being administered repeated tests were made for free autoantibodies and for
coating of the patient's cells. A progressive drop in the titer of free autoantibodies was observed, from 7 units on February 2 to 2 units* on February 8. At the same time the antiglobulin test for coating of the patient's cells became negative and the icterus index declined to 2 units. T h e patient felt well, the sedimentation rate became normal, b u t the
platelet count and the bleeding time were not improved (cf. Fig. 1). Therapy with ACTH
was stopped but improvement continued and the hemoglobin concentration rose to 10.7
Gm. and the red blood count to 3.S5 million. The patient was discharged from the hospital,
and when seen six weeks later .she still felt well and the hematologic improvement was
maintained except t h a t the sedimentation rate was again elevated. Moreover, there had
been no further purpuric manifestations, the platelet count had risen to 121,000 per cu.
mm., while the bleeding time had fallen to six minutes. However, the autoantibody titer
had risen again to 6 units. The p a t i e n t ' s condition was followed and, despite the rise in
autoantibodies, the clinical improvement continued until the platelet count, hemoglobin
concentration, red blood cell count and icterus index became normal. I t is uncertain whether
this should be credited to the splenectomy as a delayed result of the operation. The patient
has remained clinically well for a period of six months except for a short illness with tonsillitis, b u t free a u t o a n t i b o d i e s ! of low titer continue to be demonstrable with enzyme-treated
cells a t body temperature. Tests for coating of the patient's cells by autoantibodies are
weakly positive a t times. The sedimentation rate is still elevated. Her serum continues to
contain anti-Kell antibodies with a titer of about 100 units by the conglutination and antiglobulin technics.
After a complete clinical remission lasting about eight months the patient was readmitted
to the hospital because of severe pain in the left foot. In the hospital she was found.to have
* This variation, however, is within the limits of error of the technic of titration.
f We were dealing with autoantibodies and not isoantibodics, because the patient's
serum clumped the enzyme-treated cells of all persons tested, including the patient's own
cells.
TABLE 2
37 C.
5 C.
37 C.
5C.
TEMPERATURE OF
TESTS
Random group 0
Individual's own cells
Random group 0
Individual's own cells
Random group 0
Patient's own cells
Random group 0
Patient's own cells
TEST CELLS*
++±
++±
++± ++±
++± ++±
+±
tr.
+±
0 Rln
Patient's cells
0 Rhi
Patient's cells
20 C.
OC.
+++
++±
1:2
+++ +++
+++ +++
+++
+++
Undiluted
++
++
1:8
+±
++
1:16
±
+±
1:32
tr.
tr.
1:64
+ + + + + + + + + + + + :+ + +
++ + + ++ ++ + ++ + + + ±
++±
++
1:4
DILUTION OF PATIENT'S SERUM
* All titrations were carried out in saline medium against untreated red cells.
0 Rh, Patient's cells
TEST CELLS
37 C.
TEMPERATURE
TABLE 3
++±
++
1:16
++±
+ +'
1:32
++
++
1:64
++
++±
1:128
++
++±
1:256
tr.
+±
++
1:512
+±
1:256
++ + ±
1:128
TITRATION OF COLD AUTOAGGLUTININS IN A PATIENT WITH ACQUIRED HEMOLYTIC ANEMIA (CASE 3)*
++±
++
tr.
tr.
tr.
tr.
+±
+±
+±
+±
+±
++
++
++
+±
++
++
++
1:8
REACTION WITH SERUM DILUTION
1:4
1:2
Undiluted
* All test cells employed in the titrations were first treated with ficin.40
Individual with potent
cold autoantibodies
Patient (Case 2)
SERUM OF
TITRATION OF AUTOANTIBODIES IN SERUM OF PATIENT 2, IN CONTRAST TO A SERUM CONTAINING A HIGH TITER OF
COLD AUTOANTIBODIES
+
tr.
1:1024
tr.
1:512
ACQUIRED HEMOLYTIC
ANEMIA
309
a nephrotic syndrome with edema and marked albuminuria. Extreme pain in the foot
persisted and the toes became gangrenous so t h a t amputation was necessary. At the same
time the antiglobulin test for coating of the patient's red cells by autoantibodies proved to
be strongly positive, though the icterus index was low and there was no evidence of hemolysis. This suggests t h a t the gangrene of the toes was due to obstruction of the circulation
by conglutinated red cells, and supports the thesis 38 t h a t thrombotic thrombocytopenic
p u r p u r a is one of the manifestations of autoantibody disease.
Case S
Mrs. F . T., a 37-year-old white housewife was admitted to the Jewish Hospital of Brooklyn on November 2G, 1946, because of wheezing and dyspnea of 4 days' duration, cough,
headache, weakness, and a temperature ranging between 102 F. and 105 F. of ten d a y s '
duration. She was given penicillin orally with some improvement b u t became extremely
weak and developed a cold sweat for four clays before admission. She was given penicillin
intramuscularly, b u t on the clay of admission became increasingly pale.
On examination impaired percussion over the entire lung was found. Decreased breath
sounds and rales were heard over the lower portion of the left lung. A systolic murmur was
heard at the apex of the heart. T h e liver was enlarged and extended two
fingcrbreadths
below the costal margin. There was an icteric tinge to the sclerac. T h e hemoglobin concentration was 6.5 Gin., the reel blood cell count 2.2 million, and the leukocyte count 12,400.
The splenic edge was firm and extended one fingerbreadth below the costal margin. T h e
patient was found to belong to group 0 and to be Rho-positive. A transfusion of 500 ml.
of whole blood was given without untoward reaction. Despite this t h e blood count continued
to fall and the next clay the hemoglobin concentration was only 5.3 C m . and the red blood
cell count was 1.36 million. Another transfusion was ordered b u t difficulty was encountered
in the cross-matching test, and a t this time we were consulted.
Examination of the patient's blood showed t h a t her serum contained a potent cold autoantibody which had a titer of 1000 units a t refrigerator temperature, 40 units a t room
temperature, and one unit a t body temperature (cf. Table 3). In 1946, however, routine tests
were not being done by the conglutination and antiglobulin methods and with enzymetreated cells. A donor was selected of the same blood group as the patient and a test dose
of 50 ml. of blood from this donor was injected intravenously (biologic test 3 5 ). When, after
60 minutes, there were no untoward symptoms nor a rise in icterus index, a transfusion of
500 ml. of blood from this donor was given. The patient improved and later received two
additional transfusions each of 500 ml. whole blood, after which the hemoglobin concentration was 11.1 Gm. and the red blood count was 3.4 million. T h e pneumonia, which on x-ray
examination was evident as an infiltration extending from the root of the left lung into
the parenchyma, in the meantime had improved, and the patient was discharged from the
hospital on D e c e m b e r s , 1946.
T h e patient has had no recurrence of the hemolytic anemia and has remained well except for an attack of agranulocytosis due to medication with propylthiouracil in J u n e 1950.
COMMENT
It is difficult to evaluate the results of treatment in the three patients whose
case reports are presented here because of the different natures of the antibodies involved, and the differences in the intensity of the clinical symptoms. One
cannot help feeling that in the first two patients the transfusions aggravated
the symptoms, and in the first instance may have precipitated the patient's
death. This agrees with the experience of other workers, notably Young and
associates4,1 who present suggestive evidence that transfusions to patients with
"chronic hemolytic disease with erythrocyte-bound antibody" may tend to
keep the hemolytic process alive. With regard to the possible beneficial effect of
310
W I E N E R ET AL.
ACTH therapy, this is difficult to evaluate because of the tendency of this diseas 3
to have spontaneous remissions. Even in the early reports of Widal, Abrami and
Brule,32 patients with acquired hemolytic anemia recovered spontaneously from
severe hemolytic crises and had protracted remissions, and some even appeared
to be entirely cured. These cures were attributed by Widal, Abrami and Brule
to the iron they administered to these patients. The favorable results obtained
by these workers may.possibly be explained by the fact that transfusion therapy
was not yet being employed at the time, and similarly the good results obtained
by us in the patient of Case 2 may be attributable, not to ACTH therapy, but
to withholding of blood transfusion therapy.
It may be of interest to point out that all three of our patients were of the
female sex. In the original studies of Widal and associates on acquired hemolytic
anemia it was also observed that the predominance of patients was of the female
sex.
SUMMARY
A report is presented of three patients with acquired hemolytic anemia. The
first patient was a woman with "coated" red cells but without demonstrable autoantibodies or isoantibodies in her serum; she nevertheless sustained severe hemolytic reactions after transfusions of blood that was compatible in "in vitro" tests,
and died.
The second patient had thrombocytopenia in addition to anemia and icterus,
and exhibited no immediate significant improvement after splenectomy. Hemolytic transfusion reactions were explained by sensitization to the Kell (or Si)
factor, and avoided by transfusing Kell-negative blood, but the purpura did not
improve. The patient's ssrum failed to clump her own unmodified red cells at
body temperature, but autoagglutination occurred when the red cells were first
treated with proteolytic enzymes, the titer being about the same (6 to 10 units)
at body temperature and refrigerator temperature. The patient exhibited clinical
improvement when transfusions were withheld and ACTH administered. The
blood count rose but the purpura persisted. Following discharge from the hospital
the blood count and platelet count became normal. Possibly, this improvement
represents a delayed effect of the splenectomy. To date, the patient has remained
well, even though the autoantibodies are still demonstrable in low titer, the cells
have become coated again and the sedimentation rate remains elevated.
The third patient had hemolytic anemia as a complication of atypical pneumonia. The anemia was explained.by the demonstration of potent cold autoagglutinins in the patient's serum (titer 1000 units for untreated cells at refrigerator temperature, but scarcely an}' reaction at body temperature). The
patient was given four transfusions of whole blood and recovered complete^
from the anemia.
These observations illustrate the graver significance of autoantibodies which
act preferentially at body temperature even though of low titer, while the patient
of Case 3 shows that hemolytic anemia due to cold autoantibodies usually has
a good prognosis even though the antibodies are of high titer.
ACQUIRED HEMOLYTIC ANEMIA
311
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