Pancytopenia (Case 27)

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Chapter 35
Pancytopenia (Case 27)

Byron E. Crawford MD

Case: An unemployed 38-year-old woman presents with recent onset of epistaxis and lethargy. She has previously been diagnosed with gout, for which she takes colchicine, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs) during flare-ups. Because of a strong family history of cancer (mother died from breast cancer at any early age, and brother was recently diagnosed with malignant melanoma of his scalp), she is very fearful of having cancer. Physical examination reveals a pulse of 106 beats/minute (bpm), pallor of her nail beds, and several oral cavity and skin petechial hemorrhages. There is no lymphadenopathy or hepatosplenomegaly. Laboratory studies reveal a hemoglobin of 6.5 g/dL, hematocrit of 19%, platelet count of 14,000/µL, WBC count of 1800/µL with an absolute neutrophil count of 1100/µL, and a corrected reticulocyte count of 0.8%. Biochemical studies are normal, including serum LDH and uric acid concentrations.

Differential Diagnosis

Aplastic anemia


Megaloblastic anemia

Myelodysplastic syndromes



Speaking Intelligently

A very thorough history and physical examination are paramount in patients with pancytopenia, including questions regarding drugs, radiation, chemical and toxin exposure, previous and recent infections, and immunologic disorders. It may require multiple questions to elicit drug, chemical, or toxin history or exposures. Though usually not diagnostic, it is very important to review the peripheral blood smear for additional findings that may help establish a more definitive differential diagnosis. Bone marrow aspirate and biopsy to determine if the marrow is hypocellular or normocellular are also important. Pancytopenia is usually very serious, and discussion with the patient about the differential diagnosis, etiology, utilization of diagnostic tests, and therapy, both definitive and supportive, should occur.


Clinical Thinking

• Determine if the symptoms are due to a process infiltrating the bone marrow (myelophthisic anemia), or due to a primary reduction in the production of blood cells.

• Evaluation of the peripheral smear and bone marrow will usually help provide the etiology of pancytopenia.

• A marrow with an infiltrative process, such as myelofibrosis, will exhibit teardrop-shaped erythrocytes (dacrocytes), nucleated RBCs, and possibly immature myeloid precursors and giant platelets in the peripheral smear.

• The bone marrow biopsy will show increased fibrosis with either hyperplasia of all hematopoietic elements or replacement of the marrow by granulomas, tumor, or fibrosis.

• In patients with aplastic anemia, the marrow will be hypocellular or essentially acellular in regard to hematopoietic tissue, while peripheral values demonstrate pancytopenia.

• Patients with megaloblastic anemia will exhibit a macrocytic anemia with macrocytes, ovalocytes, nucleated red blood cells with nuclear-cytoplasmic asynchrony, and hypersegmented neutrophils on peripheral smear. In these patients the bone marrow will be hypercellular with erythroid hyperplasia and erythroid nuclear-cytoplasmic asynchrony. Nuclear-cytoplasmic asynchrony may also be found in myeloid and megakaryocytic precursors.

• Patients with myelodysplasia exhibit hypogranulated and hyposegmented (pseudo–Pelger-Huët) cells, neutrophils, neutrophils with Döhle bodies, and, possibly, rare blasts. A bone marrow biopsy in these patients will show variable cellularity with ringed sideroblasts, erythroid megaloblastoid dysplastic maturation, megakaryocytic dysplastic maturation, and possibly increased myeloblasts, but less than 20% of the myeloid population of the marrow.

• Patients with acute leukemia with peripheral pancytopenia will have a normocytic, normochromic anemia with hyposegmented and hypogranular neutrophils and possibly rare blasts containing Auer rods in the case of acute myeloblastic leukemia. The bone marrow will be hypercellular with greater than 20% blasts.

• In acute myeloblastic leukemia, the blast will stain or express myeloperoxidase, CD33, and CD15, while in acute lymphoblastic leukemia the blast will stain with periodic acid–Schiff (PAS) or express CD22, CD19, CD10, terminal deoxynucleotidyl transferase (TdT), and Bcl-2.

• Additional laboratory features may be helpful, such as elevated serum LDH and uric acid in megaloblastic anemia, acute leukemia, and myelofibrosis, but the evaluation of the patient’s peripheral smear and bone marrow is paramount in determining the etiology of pancytopenia.


• Many patients with pancytopenia will be asymptomatic until the anemia becomes symptomatic with malaise, vertigo, lassitude, palpitations, and weakness.

• With thrombocytopenia, the patient may present with complaints of epistaxis, easy bruising, bleeding gums, or heavy menstruation (in women).

• Other presentations of significance include weight loss (malignancy), early satiety (splenomegaly), numbness of extremities (vitamin B12/folic acid deficiency), and fever (malignancy, infection). Patients with pancytopenia usually do not present with primary infectious processes secondary to leukopenia without signs of significant anemia and thrombocytopenia.

• A medication history might reveal use of pharmacologic agents associated with bone marrow suppression including chloramphenicol, colchicine, NSAIDs, phenothiazines, thiazides, quinine, carbamazepine, phenytoin, phenylbutazone, and sulfonamides.

• Chemotherapy drugs may also result in pancytopenia.

• Chemical or toxin exposure to benzene or arsenic, and previous radiation exposure, may be found.

• Sometimes questions regarding drug, chemical, radiation, and toxin exposure must be asked multiple times in different ways to obtain a positive history.

• Past history of infectious disorders such as tuberculosis, fungal infections, HIV, hepatitis B, hepatitis C, Epstein-Barr virus (EBV), cytomegalovirus (CMV), and rarely hepatitis A may be associated with pancytopenia.

• A previous history of gastrectomy or malabsorption syndrome may be found in patients with vitamin B12 or folic acid deficiency leading to pancytopenia.

• A history of Down syndrome or Fanconi anemia may be seen in patients with myelodysplasia.

Physical Examination

• Physical examination is usually limited to features secondary to anemia and thrombocytopenia.

• Physical findings include tachycardia, pallor, possible cardiomegaly, ecchymoses, gingival bleeding, and petechial hemorrhages.

• In patients with leukemia and myelofibrosis, splenomegaly and hepatomegaly may be present.

• In patients with megaloblastic anemia, physical examination may reveal decreased vibratory sensation in the extremities, abnormal reflexes, dementia, and possible features of psychosis.

Tests for Consideration

CBC with examination of peripheral smear.


Bone marrow examination.


Bone marrow cytogenetics.


Type and screen for packed RBCs.


Serum LDH, uric acid, B12, and folic acid concentrations.

$8, $6, $21, $20

Antinuclear antibodies (ANAs), rheumatoid factor, Coombs test.

$16, $8, $8

Reticulocyte count.



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Aplastic Anemia

High-dose radiation and toxins (benzene) result in extrinsic damage to the bone marrow, while effects of moderate doses of drugs cause suppression of the marrow by altered metabolism of the pharmacologic agent. The production of toxic drug intermediates, with genetic inability for drug detoxification, may lead to marrow aplasia. Immune-mediated injury may also have a role, as certain cytokines, such as tumor necrosis factor and interferon, promote apoptosis. Cytotoxic T cells can also promote stem cell destruction.