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Mayo Clin Proc. 2010 January; 85(1): e1–e4.
PMCID: PMC2800282

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

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 concentration of approximately 10.5 g/dL. About 6 months before her referral, the patient began having recurrent episodes of severe anemia, with hemoglobin values as low as 3.5 g/dL. She had become transfusion-dependent and had received about 30 units of packed red blood cells (RBCs) in the preceding 3 months. The patient denied any history of easy bruisability, menorrhagia, or overt evidence of bleeding from any site. Additionally, she denied any change in the appearance or color of her urine and had no history of jaundice. There was no family history of anemia or any other hematologic disorder. As an outpatient, she had undergone an extensive evaluation at another institution, but results failed to provide an explanation for her anemia.

The patient's medical history was remarkable for severe asthma, thought to be due to Churg-Strauss syndrome. She had a tunneled central venous catheter for self-administration of intravenous corticosteroids at the earliest sign of an asthmatic exacerbation. Her other medications included bronchodilators, weekly erythropoietin injections, intravenous iron therapy, an antidepressant, and an anxiolytic.

At presentation, the patient's vital signs were normal. Physical examination was unremarkable except for mild generalized pallor. A complete blood count on the day of admission revealed the following (reference ranges shown parenthetically): hemoglobin, 4.9 g/dL (12.0-15.5 g/dL); mean corpuscular volume (MCV), 94.4 fL (81.6-98.3 fL); hematocrit, 13.4% (34.9%-44.5%); leukocyte count, 6.0 × 109/L (3.5-10.5 × 109/L); and platelet count, 203 × 109/L (150-450 × 109/L). The patient's partial thromboplastin time and prothrombin time (PT)/international normalized ratio were normal. These results were obtained within 24 hours of her last transfusion.

  1. Which one of the following is the least likely in the differential diagnosis of this patient's anemia?
    1. Chronic blood loss
    2. Acute hemolysis
    3. Chronic disease
    4. Myelodysplastic syndrome
    5. Acquired pure red cell aplasia
    Anemia can be categorized as microcytic, normocytic, or macrocytic by examining the MCV. This patient clearly has a normocytic anemia, with her MCV of 94.4 fL, although this must be interpreted with some caution, given her history of multiple transfusions, which can normalize the MCV. Normocytic anemias are classically due to premature destruction or acute loss of RBCs or to decreased bone marrow production. With this in mind, we can approach the proposed list of differential diagnoses. Chronic blood loss usually leads to iron deficiency anemia, which is classically microcytic in nature; however, a normocytic anemia may also be seen. Hemolytic anemias usually result in a normocytic picture. Anemia of chronic disease is usually normocytic and is possible because of this patient's complicated medical history. The myelodysplastic syndromes refer to a heterogeneous group of stem cell disorders characterized by abnormal cellular maturation and, most commonly, chronic cytopenias. They result in macrocytosis, which is classically marked, with MCV sometimes greater than 110 fL. This is the only condition listed that classically results in a macrocytic anemia, rather than normocytic, and was therefore least likely to be the cause of the patient's anemia. Acquired pure red cell aplasia is a primary bone marrow disorder characterized by decreased reticulocytes and the virtual absence of erythroid precursors in the bone marrow. It is often idiopathic but may occur in association with various diseases, such as systemic lupus erythematosus and hematologic malignancies. Regardless of the underlying cause, the anemia is usually normocytic with absolute reticulocytopenia.
    With the observation that the patient's anemia was normocytic with an MCV of 94.4 fL, the next task was to narrow the list of differential diagnoses and establish whether this was due to premature destruction or acute loss of RBCs vs decreased bone marrow production.
  2. Which one of the following would be the next best test to narrow the list of differential diagnoses?
    1. Peripheral blood smear
    2. Absolute reticulocyte count
    3. Serum ferritin
    4. Erythropoietin
    5. Bone marrow biopsy and aspiration
    The peripheral blood smear provides useful information that cannot be obtained with the usual complete blood count and can provide clues to a variety of bone marrow disorders, as well as systemic disorders that can have hematologic manifestations. However, it would not be the single best test to provide the necessary information at this point. We needed to establish whether there was an adequate or inadequate (ie, hypoproliferative) bone marrow response. An adequate response is usually due to hemolysis or acute loss of RBCs. The reticulocyte count is a good indicator of this and is the only test listed that could have directly provided this necessary piece of information. Anemia with an absolute reticulocyte count of less than 75 × 109/L provides strong evidence of deficient production of RBCs, whereas a count of greater than 100 × 109/L indicates a brisk and efficient response to hemolysis or blood loss. The region between these 2 limits remains a gray zone, and other clinical and laboratory parameters should be used to interpret the overall picture. The plasma ferritin level generally reflects overall iron storage and is typically used as a part of the panel to evaluate for iron deficiency anemia in a patient with microcytosis. Therefore, it would not be most useful in this patient with a normocytic anemia. Erythropoietin is a growth factor that is the primary stimulus for erythropoiesis. It would not be useful at this juncture in revealing whether the anemia is due to decreased production or increased loss of blood cells or premature destruction. A bone marrow biopsy would show erythroid hyperplasia, a nonspecific finding, if erythropoiesis is increased in response to the anemia. If there is a hypoproliferative state, the marrow may reveal a variety of findings, depending on the underlying diagnosis. Therefore, a bone marrow biopsy would be premature at this point. However, a bone marrow biopsy would be indicated if there was pancytopenia or if the peripheral smear showed abnormal cells, such as blast forms or dysplastic changes.
    Our patient had a reticulocytosis of 13.3% (0.60%-1.83%), with an absolute reticulocyte count of 238.8 × 109/L (29.5-87.3 × 109/L).
  3. At this time, which one of the following series of tests would be most helpful in further narrowing the differential diagnosis?
    1. Total and indirect bilirubin levels, haptoglobin, lactate dehydrogenase (LDH)
    2. Peripheral blood smear
    3. Direct Coombs test
    4. Indirect Coombs test
    5. Activated partial thromboplastin time (aPTT), PT, fibrinogen, soluble fibrin monomer complex, and D-dimers
    In this patient with an absolute reticulocytosis, ie, an adequate bone marrow response, the next step would be in differentiating between hemolysis and acute blood loss. Hemolysis is usually characterized by elevated indirect bilirubin concentrations, decreased serum haptoglobin concentrations (with intravascular hemolysis in particular), and increased serum LDH levels, and this series of tests would be most useful in narrowing the differential diagnoses at this point. The peripheral blood smear is less specific, but in the presence of hemolysis, it may reveal abnormally shaped RBCs, including fragmented RBCs (schistocytes, helmet cells), spherocytes, elliptocytes, or RBC inclusions, which may be seen in certain hemolysis-producing infections, such as malaria, babesiosis, and Bartonella. Hemolytic anemias may be acquired and immune, in which case there is immunologic destruction of RBCs mediated by autoantibodies directed against antigens on the patient's RBCs. The direct and indirect Coombs tests detect antibodies on the surface of the patient's RBCs and in the patient's serum, respectively. However, the presence of hemolysis must first be established, especially since a patient may have a mildly positive Coombs test that is clinically insignificant if not associated with ongoing hemolysis. The laboratory findings in disseminated intravascular coagulation and intravascular coagulation and fibrinolysis (DIC/ICF) include elevated D-dimer and soluble fibrin monomer complex levels, low fibrinogen levels, and prolonged PT and aPTT. Therefore, these investigations should be performed when a diagnosis of DIC/ICF is suspected. However, this patient's clinical scenario and laboratory findings to date, ie, lack of thrombocytopenia and normal PT and aPTT, do not suggest underlying DIC/ICF.
    The patient had a mildly reduced haptoglobin level at 14 mg/dL (30-200 mg/dL), likely secondary to her multiple transfusions. However, her LDH level was normal at 205 U/L (122-222 U/L), as were her total and direct bilirubin levels at 0.4 mg/dL (0.1-1.0 mg/dL) and 0.1 mg/dL (0.0-0.3 mg/dL), respectively. A peripheral blood smear showed no abnormally shaped RBCs. The overall picture was not in keeping with hemolysis. On the first day of her evaluation, the patient's hemoglobin concentration was 11.1 g/dL. By 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 transfusions, her hemoglobin concentration decreased further within 24 hours to 4.9 g/dL. At this point, the patient was admitted and received 3 more units of packed RBCs. During this time, she was asymptomatic, and her vital signs remained stable.
  4. At this point, which one of the following would be the best step in the management of this patient?
    1. Esophagogastroduodenoscopy
    2. Colonoscopy
    3. Computed tomography (CT) of the abdomen and pelvis
    4. Transfer to the intensive care unit
    5. Angiography of the gastrointestinal (GI) tract
    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. However, the patient could have occult intra-abdominal bleeding, and noncontrast CT of her abdomen and pelvis would be crucial in ruling this out. The patient's mental status remained 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 be unnecessary at this time. She was well compensated despite the severity and acuteness of the anemia, no doubt in part due to her age and lack of other cardiac comorbidities. In this patient who is exhibiting no overt evidence of GI bleeding, angiography would not be the next best step.
    Noncontrast CT of her abdomen and pelvis revealed normal findings. During the night of hospital day 2, an astute nurse noticed what appeared to be bloodstains on the patient's gown. The patient reported that she had spilled cranberry juice on the gown. Closer inspection of her room revealed several blood-soaked tissues and Styrofoam cups filled with fresh blood in her wastebasket. The patient was also found to have dried, crusted blood all over her fingernails, and a blood-stained 10-mL syringe, most of its labeling worn away by overuse, was found in her gown pocket (Figure).
    FIGURE.
    10-mL syringe allegedly used by the patient for self-phlebotomy.
  5. Which one of the following is the most likely cause of this patient's anemia?
    1. Factitious disorder
    2. Munchausen by proxy
    3. Malingering
    4. Somatization disorder
    5. Hypochondriasis
    With the discovery made in the patient's room, in particular the syringe, the patient's self-phlebotomy became evident, leading to a diagnosis of factitious anemia. The most chronic and extreme form of factitious illness, Munchausen syndrome, typically includes travel from hospital to hospital combined with the willingness to submit to multiple procedures for self-fabricated signs of illness, as occurred with our patient before her presentation at our institution. In Munchausen by proxy, caregivers (usually mothers) induce illness in their children to obtain care and support for themselves. In malingering, illness is feigned to gain such external incentives as money or drugs or to avoid such consequences as military service or criminal prosecution. Factitious disorder, in contrast, has no incentive other than being a patient in the sick role. Since we identified no incentive other than obtaining our care, our patient could not be said to be malingering. Somatization refers to the tendency to experience psychological distress in the form of somatic symptoms not intentionally produced, thus differentiating this disorder from factitious illness or malingering. Hypochondriasis refers to a preoccupation with believing one is ill as a result of misconstruing physical symptoms that are not self-generated. By her self-phlebotomizing activity, our patient could not be considered hypochondriacal.
    The patient was seen by the psychiatry service, and although she was obviously at risk of purposeful self-harm, she denied suicidal or homicidal ideation. It became evident that she had a history of severe depression, borderline personality disorder, chemical dependency, and a history of repeated episodes of parasuicide by means of wrist cutting. She gave consent for her central line to be removed, and this was done before her dismissal. There was direct communication with her primary care physicians and primary psychiatrist, and she was then dismissed from the hospital with a plan for close and consistent medical attention.

DISCUSSION

Several cases of factitious anemia have been reported in the literature.1,2 The patient is seldom caught in the act and usually denies the behavior, making the diagnosis difficult to establish incontrovertibly. Patients with this condition often have underlying psychiatric issues and constantly need to assume the sick role. Once the diagnosis is suspected, the patient should be confronted, and removal of any contributing medical device is essential. Early diagnosis is usually difficult but may prevent repeated hospitalizations and the risks associated with invasive diagnostic procedures.2 Management is usually extremely difficult but should be centered around long-term psychotherapy.2 A multidisciplinary approach is of utmost importance because patients usually become very uncooperative when they are discovered and may make attempts to break off relations with the current medical staff and seek medical attention elsewhere. Providing optimal management to an uncooperative patient may be difficult without violating the patient's autonomy. Therefore, a psychiatric consultation should be arranged as soon as possible, and seeking assistance from the institution's ethics and legal committees may be prudent.

The current case provides an opportunity to highlight an approach to the patient presenting with anemia. Anemia can be classified according to measurement of RBC size, as seen on the peripheral blood smear and as indicated by the MCV. This morphological approach categorizes the anemias as microcytic, normocytic, or macrocytic, providing a useful starting point to narrow the list of differential diagnoses. By definition, the MCV is normal (80-100 fL) in patients with normocytic anemia, low (<80 fL) in patients with microcytic anemia, and high (>100 fL) in patients with macrocytic anemia.3

The presence of a microcytic anemia usually indicates a pathologic process involving hemoglobin synthesis. The most common cause is iron deficiency, but other classic causes include the thalassemias and other hemoglobinopathies, lead poisoning, sideroblastic anemia, and, less commonly, anemia of chronic disease. If microcytosis is identified, the next step would be to differentiate among these common causes, and this can be done by assessing serum iron studies, which include serum ferritin, iron, total iron-binding capacity, and transferrin saturation. In iron deficiency, the classic findings are a low serum ferritin value, which is diagnostic, elevated total iron-binding capacity, and low saturation. Other findings include a peripheral blood smear showing anisocytosis and poikilocytosis. If the serum ferritin level and other iron studies are normal, then thalassemia should be considered, and hemoglobin electrophoresis should be performed for the definitive diagnosis. Caution must be taken in interpreting the iron studies in anemia of chronic disease because findings are often inconsistent. The entire clinical scenario must be taken into account.3 Sideroblastic anemias may be hereditary or acquired, and the latter is characterized by increased RBC distribution width, dimorphic RBCs, and bone marrow ringed sideroblasts.

If the anemia is found to be normocytic, the next step would be to differentiate between RBC destruction/loss and a hypoproliferative state. The presence of an increased reticulocyte response (>100 × 109/L) suggests either loss or destruction of RBCs; thus, differentiation of these 2 conditions must be made. Hemolysis is characterized by elevated indirect bilirubin levels, decreased serum haptoglobin levels, and increased serum LDH levels. Also, the peripheral smear may reveal several abnormalities, such as fragmented RBCs and other abnormally shaped RBCs. If laboratory parameters or the peripheral smear is not suggestive of hemolysis, then a bleeding source should be sought. A normocytic anemia without reticulocytosis indicates an aplastic anemia; myelophthisis in which the bone marrow is replaced by fibrosis, tumor, or other abnormal cells; or lack of erythropoietin, which can be seen classically in renal failure.

The first step in evaluating a macrocytic anemia should be ruling out a marked reticulocytosis (polychromasia). Polychromasia may cause a regenerative macrocytosis. If this is found, evaluation for hemolysis or blood loss should be performed as outlined previously. Macrocytic anemias may be due to defects in DNA synthesis, resulting in oval macrocytes, or increase in the cholesterol/phospholipid ratio in membranes, resulting in round macrocytes.

Oval macrocytosis is classically due to vitamin B12 or folate deficiency. If neither is present, then a bone marrow biopsy is warranted to look for the presence of a myelodysplastic syndrome. Round macrocytes may be due to severe alcoholism, liver disease, or hypothyroidism. Also, tobacco use and advanced age may result in round macrocytosis without anemia.

Factitious disorders are difficult to diagnose. However, our patient presented with several clues, including her previous psychiatric history and the recurrent dramatic decreases in her hemoglobin concentration, usually when she was unsupervised. Heightened suspicion is the first step in arriving at the correct diagnosis. Additionally, if anemia is approached in a logical stepwise manner, as outlined previously, multiple expensive, unnecessary, and invasive investigations can be avoided, and if due to a factitious disorder, necessary psychotherapy can be implemented in a more timely fashion.

Acknowledgments

We thank J. Michael Bostwick MD, Department of Psychiatry, Mayo Clinic, Rochester MN, for his expertise in the care of this patient and guidance in the preparation of the submitted manuscript.

Notes

See end of article for correct answers to questions.

Correct answers: 1. d, 2. b, 3. a, 4. c, 5. a

REFERENCES

1. Abram HS. Hollender MH Factitious blood disease. South Med J 1974;67(6):691-696 [PubMed]
2. Haddad SA, Winer KK, Gupta A, Chakrabarti S, Noel P, Klein HG. A puzzling case of anemia. Transfusion 2002;42(12):1610-1613 [PubMed]
3. Tefferi A. Anemia in adults: a contemporary approach to diagnosis. Mayo Clin Proc 2003;78(10):1274-1280 [PubMed]

Articles from Mayo Clinic Proceedings are provided here courtesy of The Mayo Foundation for Medical Education and Research