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39-Year-Old Woman With an Obscure Case of Anemia

Shanique R. Palmer, MBBS*; Gita Thanarajasingam, MD†; and Alexandra P. Wolanskyj, MD‡

A 39-year-old woman was referred to our institution for

evaluation of anemia. She was known to have multiple
comorbidities and had a baseline hemoglobin concentra-
multiple transfusions, which can normalize the MCV. Nor-
mocytic anemias are classically due to premature destruction
or acute loss of RBCs or to decreased bone marrow produc-
tion of approximately 10.5 g/dL. About 6 months before tion. With this in mind, we can approach the proposed list
her referral, the patient began having recurrent episodes of differential diagnoses. Chronic blood loss usually leads
of severe anemia, with hemoglobin values as low as 3.5 to iron deficiency anemia, which is classically microcytic
g/dL. She had become transfusion-dependent and had re- in nature; however, a normocytic anemia may also be seen.
ceived about 30 units of packed red blood cells (RBCs) in Hemolytic anemias usually result in a normocytic picture.
the preceding 3 months. The patient denied any history of Anemia of chronic disease is usually normocytic and is pos-
easy bruisability, menorrhagia, or overt evidence of bleed- sible because of this patient’s complicated medical history.
ing from any site. Additionally, she denied any change in The myelodysplastic syndromes refer to a heterogeneous
the appearance or color of her urine and had no history of group of stem cell disorders characterized by abnormal cel-
jaundice. There was no family history of anemia or any lular maturation and, most commonly, chronic cytopenias.
other hematologic disorder. As an outpatient, she had un- They result in macrocytosis, which is classically marked,
dergone an extensive evaluation at another institution, but with MCV sometimes greater than 110 fL. This is the only
results failed to provide an explanation for her anemia. condition listed that classically results in a macrocytic ane-
The patient’s medical history was remarkable for severe mia, rather than normocytic, and was therefore least likely
asthma, thought to be due to Churg-Strauss syndrome. She to be the cause of the patient’s anemia. Acquired pure red
had a tunneled central venous catheter for self-administra- cell aplasia is a primary bone marrow disorder characterized
tion of intravenous corticosteroids at the earliest sign of by decreased reticulocytes and the virtual absence of eryth-
an asthmatic exacerbation. Her other medications included roid precursors in the bone marrow. It is often idiopathic but
bronchodilators, weekly erythropoietin injections, intrave- may occur in association with various diseases, such as sys-
nous iron therapy, an antidepressant, and an anxiolytic. temic lupus erythematosus and hematologic malignancies.
At presentation, the patient’s vital signs were normal. Regardless of the underlying cause, the anemia is usually
Physical examination was unremarkable except for mild normocytic with absolute reticulocytopenia.
generalized pallor. A complete blood count on the day of With the observation that the patient’s anemia was nor-
admission revealed the following (reference ranges shown mocytic with an MCV of 94.4 fL, the next task was to nar-
parenthetically): hemoglobin, 4.9 g/dL (12.0-15.5 g/dL); row the list of differential diagnoses and establish whether
mean corpuscular volume (MCV), 94.4 fL (81.6-98.3 fL); this was due to premature destruction or acute loss of RBCs
hematocrit, 13.4% (34.9%-44.5%); leukocyte count, 6.0 × vs decreased bone marrow production.
109/L (3.5-10.5 × 109/L); and platelet count, 203 × 109/L
2. Which one of the following would be the next best test
(150-450 × 109/L). The patient’s partial thromboplastin
to narrow the list of differential diagnoses?
time and prothrombin time (PT)/international normalized
a. Peripheral blood smear
ratio were normal. These results were obtained within 24
b. Absolute reticulocyte count
hours of her last transfusion.
c. Serum ferritin
1. Which one of the following is the least likely in the dif- d. Erythropoietin
ferential diagnosis of this patient’s anemia? e. Bone marrow biopsy and aspiration
a. Chronic blood loss
b. Acute hemolysis *Resident in Internal Medicine, Mayo School of Graduate Medical Education,
c. Chronic disease Mayo Clinic, Rochester, MN.
†Medical student, Mayo Medical School, Rochester, MN.
d. Myelodysplastic syndrome ‡Adviser to fellow and Consultant in Hematology, Mayo Clinic, Rochester,
e. Acquired pure red cell aplasia MN.
See end of article for correct answers to questions.
Anemia can be categorized as microcytic, normocytic, or
Individual reprints of this article are not available. Address correspondence
macrocytic by examining the MCV. This patient clearly has a to Alexandra P. Wolanskyj, MD, Division of Hematology, Mayo Clinic, 200 First
normocytic anemia, with her MCV of 94.4 fL, although this St SW, Rochester, MN 55905 (wolanskyj.alexandra@mayo.edu).
must be interpreted with some caution, given her history of © 2009 Mayo Foundation for Medical Education and Research

Mayo Clin Proc. • January 2010;85(1):e1-e4 • doi:10.4065/mcp.2008.0721 • www.mayoclinicproceedings.com e1

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The peripheral blood smear provides useful information lysis is usually characterized by elevated indirect bilirubin
that cannot be obtained with the usual complete blood count concentrations, decreased serum haptoglobin concentrations
and can provide clues to a variety of bone marrow disor- (with intravascular hemolysis in particular), and increased
ders, as well as systemic disorders that can have hematologic serum LDH levels, and this series of tests would be most
manifestations. However, it would not be the single best test useful in narrowing the differential diagnoses at this point.
to provide the necessary information at this point. We need- The peripheral blood smear is less specific, but in the pres-
ed to establish whether there was an adequate or inadequate ence of hemolysis, it may reveal abnormally shaped RBCs,
(ie, hypoproliferative) bone marrow response. An adequate including fragmented RBCs (schistocytes, helmet cells),
response is usually due to hemolysis or acute loss of RBCs. spherocytes, elliptocytes, or RBC inclusions, which may
The reticulocyte count is a good indicator of this and is the be seen in certain hemolysis-producing infections, such as
only test listed that could have directly provided this neces- malaria, babesiosis, and Bartonella. Hemolytic anemias
sary piece of information. Anemia with an absolute reticulo- may be acquired and immune, in which case there is im-
cyte count of less than 75 × 109/L provides strong evidence munologic destruction of RBCs mediated by autoantibodies
of deficient production of RBCs, whereas a count of greater directed against antigens on the patient’s RBCs. The direct
than 100 × 109/L indicates a brisk and efficient response to and indirect Coombs tests detect antibodies on the surface of
hemolysis or blood loss. The region between these 2 lim- the patient’s RBCs and in the patient’s serum, respectively.
its remains a gray zone, and other clinical and laboratory However, the presence of hemolysis must first be estab-
parameters should be used to interpret the overall picture. lished, especially since a patient may have a mildly positive
The plasma ferritin level generally reflects overall iron stor- Coombs test that is clinically insignificant if not associated
age and is typically used as a part of the panel to evaluate with ongoing hemolysis. The laboratory findings in dissemi-
for iron deficiency anemia in a patient with microcytosis. nated intravascular coagulation and intravascular coagula-
Therefore, it would not be most useful in this patient with tion and fibrinolysis (DIC/ICF) include elevated D-dimer
a normocytic anemia. Erythropoietin is a growth factor that and soluble fibrin monomer complex levels, low fibrinogen
is the primary stimulus for erythropoiesis. It would not be levels, and prolonged PT and aPTT. Therefore, these inves-
useful at this juncture in revealing whether the anemia is due tigations should be performed when a diagnosis of DIC/ICF
to decreased production or increased loss of blood cells or is suspected. However, this patient’s clinical scenario and
premature destruction. A bone marrow biopsy would show laboratory findings to date, ie, lack of thrombocytopenia and
erythroid hyperplasia, a nonspecific finding, if erythropoiesis normal PT and aPTT, do not suggest underlying DIC/ICF.
is increased in response to the anemia. If there is a hypopro- The patient had a mildly reduced haptoglobin level at
liferative state, the marrow may reveal a variety of findings, 14 mg/dL (30-200 mg/dL), likely secondary to her multiple
depending on the underlying diagnosis. Therefore, a bone transfusions. However, her LDH level was normal at 205
marrow biopsy would be premature at this point. However, U/L (122-222 U/L), as were her total and direct bilirubin
a bone marrow biopsy would be indicated if there was pan- levels at 0.4 mg/dL (0.1-1.0 mg/dL) and 0.1 mg/dL (0.0-0.3
cytopenia or if the peripheral smear showed abnormal cells, mg/dL), respectively. A peripheral blood smear showed no
such as blast forms or dysplastic changes. abnormally shaped RBCs. The overall picture was not in
Our patient had a reticulocytosis of 13.3% (0.60%- keeping with hemolysis. On the first day of her evaluation,
1.83%), with an absolute reticulocyte count of 238.8 × the patient’s hemoglobin concentration was 11.1 g/dL. By
109/L (29.5-87.3 × 109/L). day 2 of her outpatient work-up, it had decreased to 5.6 g/
dL, and she received 4 units of packed RBCs. Despite the
3. At this time, which one of the following series of tests
transfusions, her hemoglobin concentration decreased fur-
would be most helpful in further narrowing the differ-
ther within 24 hours to 4.9 g/dL. At this point, the patient
ential diagnosis?
was admitted and received 3 more units of packed RBCs.
a. Total and indirect bilirubin levels, haptoglobin, lactate
During this time, she was asymptomatic, and her vital signs
dehydrogenase (LDH)
remained stable.
b. Peripheral blood smear
c. Direct Coombs test 4. At this point, which one of the following would be the
d. Indirect Coombs test best step in the management of this patient?
e. Activated partial thromboplastin time (aPTT), PT, fibrin- a. Esophagogastroduodenoscopy
ogen, soluble fibrin monomer complex, and D-dimers b. Colonoscopy
In this patient with an absolute reticulocytosis, ie, an ad- c. Computed tomography (CT) of the abdomen and pelvis
equate bone marrow response, the next step would be in dif- d. Transfer to the intensive care unit
ferentiating between hemolysis and acute blood loss. Hemo- e. Angiography of the gastrointestinal (GI) tract

e2 Mayo Clin Proc. • January 2010;85(1):e1-e4 • doi:10.4065/mcp.2008.0721 • www.mayoclinicproceedings.com

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The patient had no overt signs or symptoms of bleeding,

and it would be unlikely for her to have occult GI bleeding
that resulted in such dramatic decreases in her hemoglobin
concentration. Also, results of fecal occult blood testing were
negative. Therefore, neither upper nor lower GI endoscopy
would be expected to reveal any useful information. How-
ever, the patient could have occult intra-abdominal bleed-
ing, and noncontrast CT of her abdomen and pelvis would
be crucial in ruling this out. The patient’s mental status re-
mained normal, and she was exhibiting no overt evidence of
decreased perfusion or hemodynamic instability other than
mild tachycardia. Therefore, she could be deemed clinically
stable, and transferring her to the intensive care unit would FIGURE. 10-mL syringe allegedly used by the patient for self-
be unnecessary at this time. She was well compensated de- phlebotomy.
spite the severity and acuteness of the anemia, no doubt in
part due to her age and lack of other cardiac comorbidities. tive other than obtaining our care, our patient could not be
In this patient who is exhibiting no overt evidence of GI said to be malingering. Somatization refers to the tendency
bleeding, angiography would not be the next best step. to experience psychological distress in the form of somatic
Noncontrast CT of her abdomen and pelvis revealed symptoms not intentionally produced, thus differentiating
normal findings. During the night of hospital day 2, an as- this disorder from factitious illness or malingering. Hypo-
tute nurse noticed what appeared to be bloodstains on the chondriasis refers to a preoccupation with believing one
patient’s gown. The patient reported that she had spilled is ill as a result of misconstruing physical symptoms that
cranberry juice on the gown. Closer inspection of her room are not self-generated. By her self-phlebotomizing activity,
revealed several blood-soaked tissues and Styrofoam cups our patient could not be considered hypochondriacal.
filled with fresh blood in her wastebasket. The patient was The patient was seen by the psychiatry service, and al-
also found to have dried, crusted blood all over her finger- though she was obviously at risk of purposeful self-harm,
nails, and a blood-stained 10-mL syringe, most of its label- she denied suicidal or homicidal ideation. It became evi-
ing worn away by overuse, was found in her gown pocket dent that she had a history of severe depression, borderline
(Figure). personality disorder, chemical dependency, and a history of
repeated episodes of parasuicide by means of wrist cutting.
5. Which one of the following is the most likely cause of
She gave consent for her central line to be removed, and
this patient’s anemia?
this was done before her dismissal. There was direct com-
a. Factitious disorder
munication with her primary care physicians and primary
b. Munchausen by proxy
psychiatrist, and she was then dismissed from the hospital
c. Malingering
with a plan for close and consistent medical attention.
d. Somatization disorder
e. Hypochondriasis
DISCUSSION
With the discovery made in the patient’s room, in partic-
ular the syringe, the patient’s self-phlebotomy became evi- Several cases of factitious anemia have been reported in
dent, leading to a diagnosis of factitious anemia. The most the literature.1,2 The patient is seldom caught in the act and
chronic and extreme form of factitious illness, Munchausen usually denies the behavior, making the diagnosis difficult
syndrome, typically includes travel from hospital to hos- to establish incontrovertibly. Patients with this condition of-
pital combined with the willingness to submit to multiple ten have underlying psychiatric issues and constantly need
procedures for self-fabricated signs of illness, as occurred to assume the sick role. Once the diagnosis is suspected, the
with our patient before her presentation at our institution. patient should be confronted, and removal of any contribut-
In Munchausen by proxy, caregivers (usually mothers) in- ing medical device is essential. Early diagnosis is usually
duce illness in their children to obtain care and support for difficult but may prevent repeated hospitalizations and the
themselves. In malingering, illness is feigned to gain such risks associated with invasive diagnostic procedures.2 Man-
external incentives as money or drugs or to avoid such con- agement is usually extremely difficult but should be cen-
sequences as military service or criminal prosecution. Fac- tered around long-term psychotherapy.2 A multidisciplinary
titious disorder, in contrast, has no incentive other than be- approach is of utmost importance because patients usually
ing a patient in the sick role. Since we identified no incen- become very uncooperative when they are discovered and

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a Clinic Proceedings.
e-Residents' clinic

may make attempts to break off relations with the current and increased serum LDH levels. Also, the peripheral smear
medical staff and seek medical attention elsewhere. Provid- may reveal several abnormalities, such as fragmented RBCs
ing optimal management to an uncooperative patient may be and other abnormally shaped RBCs. If laboratory param-
difficult without violating the patient’s autonomy. Therefore, eters or the peripheral smear is not suggestive of hemoly-
a psychiatric consultation should be arranged as soon as pos- sis, then a bleeding source should be sought. A normocytic
sible, and seeking assistance from the institution’s ethics and anemia without reticulocytosis indicates an aplastic anemia;
legal committees may be prudent. myelophthisis in which the bone marrow is replaced by fi-
The current case provides an opportunity to highlight brosis, tumor, or other abnormal cells; or lack of erythropoi-
an approach to the patient presenting with anemia. Anemia etin, which can be seen classically in renal failure.
can be classified according to measurement of RBC size, The first step in evaluating a macrocytic anemia should
as seen on the peripheral blood smear and as indicated by be ruling out a marked reticulocytosis (polychromasia).
the MCV. This morphological approach categorizes the Polychromasia may cause a regenerative macrocytosis. If
anemias as microcytic, normocytic, or macrocytic, provid- this is found, evaluation for hemolysis or blood loss should
ing a useful starting point to narrow the list of differential be performed as outlined previously. Macrocytic anemias
diagnoses. By definition, the MCV is normal (80-100 fL) in may be due to defects in DNA synthesis, resulting in oval
patients with normocytic anemia, low (<80 fL) in patients macrocytes, or increase in the cholesterol/phospholipid ra-
with microcytic anemia, and high (>100 fL) in patients with tio in membranes, resulting in round macrocytes.
macrocytic anemia.3 Oval macrocytosis is classically due to vitamin B12 or
The presence of a microcytic anemia usually indicates a folate deficiency. If neither is present, then a bone marrow
pathologic process involving hemoglobin synthesis. The most biopsy is warranted to look for the presence of a myelodys-
common cause is iron deficiency, but other classic causes in- plastic syndrome. Round macrocytes may be due to severe
clude the thalassemias and other hemoglobinopathies, lead alcoholism, liver disease, or hypothyroidism. Also, tobacco
poisoning, sideroblastic anemia, and, less commonly, ane- use and advanced age may result in round macrocytosis
mia of chronic disease. If microcytosis is identified, the next without anemia.
step would be to differentiate among these common causes, Factitious disorders are difficult to diagnose. However, our
and this can be done by assessing serum iron studies, which patient presented with several clues, including her previous
include serum ferritin, iron, total iron- binding capacity, and psychiatric history and the recurrent dramatic decreases in
transferrin saturation. In iron deficiency, the classic findings her hemoglobin concentration, usually when she was unsu-
are a low serum ferritin value, which is diagnostic, elevated pervised. Heightened suspicion is the first step in arriving at
total iron-binding capacity, and low saturation. Other find- the correct diagnosis. Additionally, if anemia is approached
ings include a peripheral blood smear showing anisocytosis in a logical stepwise manner, as outlined previously, mul-
and poikilocytosis. If the serum ferritin level and other iron tiple expensive, unnecessary, and invasive investigations can
studies are normal, then thalassemia should be considered, be avoided, and if due to a factitious disorder, necessary psy-
and hemoglobin electrophoresis should be performed for the chotherapy can be implemented in a more timely fashion.
definitive diagnosis. Caution must be taken in interpreting
the iron studies in anemia of chronic disease because find- We thank J. Michael Bostwick MD, Department of Psychiatry,
ings are often inconsistent. The entire clinical scenario must Mayo Clinic, Rochester MN, for his expertise in the care of this pa-
be taken into account.3 Sideroblastic anemias may be heredi- tient and guidance in the preparation of the submitted manuscript.
tary or acquired, and the latter is characterized by increased
RBC distribution width, dimorphic RBCs, and bone marrow
References
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1. Abram HS. Hollender MH Factitious blood disease. South Med J. 1974;
If the anemia is found to be normocytic, the next step 67(6):691-696.
would be to differentiate between RBC destruction/loss and 2. Haddad SA, Winer KK, Gupta A, Chakrabarti S, Noel P, Klein HG. A puz-
zling case of anemia. Transfusion. 2002;42(12):1610-1613.
a hypoproliferative state. The presence of an increased re-
3. Tefferi A. Anemia in adults: a contemporary approach to diagnosis. Mayo
ticulocyte response (>100 × 109/L) suggests either loss or Clin Proc. 2003;78(10):1274-1280.
destruction of RBCs; thus, differentiation of these 2 condi-
tions must be made. Hemolysis is characterized by elevated
indirect bilirubin levels, decreased serum haptoglobin levels, Correct answers: 1. d, 2. b, 3. a, 4. c, 5. a

e4 Mayo Clin Proc. • January 2010;85(1):e1-e4 • doi:10.4065/mcp.2008.0721 • www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.