Pancytopenia

The Saint-Chopra Guide to Inpatient

Medicine (4 ed.)
Edited by Sanjay Saint and Vineet Chopra

Publisher: Oxford University Press Print Publication Date: Nov 2018

Print ISBN-13: 9780190862800 Published online: Nov 2018
DOI: 10.1093/med/ Sanjay Saint and Vineet Chopra 2019
9780190862800.001.0001

Pancytopenia  

Chapter: Pancytopenia

Author(s): Dale Bixby

DOI: 10.1093/med/9780190862800.003.0059

A. Introduction. Pancytopenia is defined as a reduction in all blood

cell lines.
B. Clinical Manifestations of Pancytopenia
a. Pancytopenia usually presents with signs and symptoms that
relate to a reduction in a particular cell line.
i. Anemia
1. Defined as a hemoglobin <13.5 g/dL or a
hematocrit <41.0% in men and a hemoglobin <12.0
g/dL or hematocrit <36.0% in women in most
laboratories.
2. Can result in increased fatigue, shortness of
breath, lightheadedness, and pallor.

ii. Thrombocytopenia
1. Defined as a platelet count of <150,000 cells/μL.
2. Patients with platelet counts >100,000 cells/μL
often have normal bleeding times (unless platelet
function is abnormal) and usually do not have
symptoms.

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Pancytopenia

3. Easy bruising may be noted as the platelet count

approaches 50,000 cells/μL.
4. Counts below 10,000–20,000 cells/μL can be
associated with petechiae, mucosal bleeding,
hemarthrosis, and spontaneous internal bleeds.

iii. Neutropenia
1. Defined as an absolute neutrophil count of <1500
cells/μL.
2. Predisposes patients to bacterial infections
(however, patients usually present with symptoms
related to anemia or thrombocytopenia first).
3. The risk for infection increases substantially after
the neutrophil count falls below 500 cells/μL.

b. Disease-specific symptoms (e.g., neurologic symptoms in

vitamin B12 deficiency, cachexia in malignancy) may also be
present.
Hot Key
Pancytopenia is a great reminder that even mild,
nonspecific symptoms can be the harbinger of a serious
illness. You should therefore consider getting a complete
blood count (CBC) with a differential on all patients with
a prolonged or recurring illness.

C. Causes of Pancytopenia. Many textbooks attempt to

differentiate causes of decreased production from those of increased
destruction. For pancytopenia, this distinction is not very useful
because both processes are often involved. The mnemonic
“PANCYTO” can help you remember the most common causes of
pancytopenia.
MNEMONIC: Common Causes of Pancytopenia (“PANCYTO”)
Paroxysmal nocturnal hemoglobinuria (PNH)
Aplastic anemia
Neoplasms and Near neoplasms
Consumption
Vitamin deficiencies (the “V” looks like a “Y”)
Toxins, drugs, and radiation therapy
Overwhelming infections

a. PNH is a disorder of stem cells that results in an increased

sensitivity to complement-mediated cell lysis. The etiology
relates to a somatically acquired loss of the PIGA
(phosphatidylinositol N-acetylglucosaminyltransferase subunit
A) gene in hematopoietic progenitor cells. PNH can clinically
manifest as an isolated Coombs test–negative intravascular
hemolysis, a hypercoagulable state, and/or bone marrow
aplasia.

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Pancytopenia

b. Aplastic anemia is one of the misnomers in medicine

because it involves a disorder of stem cells and therefore
affects all cell lines. The etiology of idiopathic aplastic anemia
is unknown, but an immune-mediated reduction in
hematopoietic progenitors has been proposed. Exposures and
secondary disorders associated with aplastic anemia are listed
next; many cases of aplastic anemia have no identifiable cause.
i. Fanconi’s anemia is an autosomal recessive or X-linked
disease that usually appears in childhood and is often
associated with other congenital abnormalities (e.g.,
cardiac and renal malformations, hypoplastic thumbs,
hyperpigmented skin). Fanconi’s anemia is associated with
an increased risk for solid tumors and leukemias as well as
aplastic anemia.
ii. Drugs and toxins. Chemotherapeutic agents,
chloramphenicol, sulfa drugs, gold, nonsteroidal
antiinflammatory drugs, certain antiepileptic drugs,
ionizing radiation, benzene, and various other drugs have
been associated with aplastic anemia.
iii. Infections. Parvovirus B19 is the most frequently
documented viral cause of aplastic anemia. Hepatitis, HIV,
cytomegalovirus (CMV), and, Epstein-Barr virus (EBV)
infections have also been seen; however, the specific type
of hepatitis virus associated with aplastic anemia has not
been identified.
iv. Immune disorders. Disorders of the immune system
and immune dysregulation may also play a role in the
development of aplastic anemia.
v. Idiopathic. Despite an extensive workup, the cause
remains unclear in a large number of patients. In these
cases, the leading hypothesis is that a host immune
response against hematopoietic progenitor cells leads to
the aplastic anemia.

c. Neoplasms (e.g., leukemia, metastatic malignancies) and

near neoplasms (i.e., myelodysplastic syndrome) can cause
pancytopenia.
d. Consumption
i. Hypersplenism (see Chapter 31).
ii. Immune-mediated destruction usually results in
decreases of one or two cell lines but can also cause
pancytopenia.

e. Vitamin deficiencies (e.g., vitamin B12 and folate

deficiencies) should always be considered in patients with
pancytopenia.
f. Toxins, drugs, and radiation therapy. For example, ethanol
use may result in pancytopenia. Many chemotherapeutic

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Pancytopenia

agents, and commonly used medications such as

chloramphenicol and linezolid can also cause pancytopenia
g. Overwhelming infections. Sepsis, tuberculosis, or fungal
infection can cause pancytopenia. HIV infection can also result
in pancytopenia from the infection itself, superimposed
infections, or medications used to treat the infection.

D. Approach to the Patient

Hot Key
Pancytopenia should be considered a primary bone marrow
failure until proven otherwise.

a. Patient history. Inquire about medications, exposures, and

HIV risk factors. Perform a review of systems, asking the
patient about cachexia and other symptoms of an occult
malignancy. Inquire about recent bruising, bleeding, or
recurrent infections.
b. Physical examination. Carefully examine the spleen and
lymph nodes. The presence of splenomegaly increases the
likelihood of malignancy and essentially rules out aplastic
anemia.
c. Laboratory studies. Although a bone marrow biopsy is
usually necessary to establish the diagnosis, in some patients, a
routine peripheral blood smear and other less invasive tests
may be helpful.
i. Peripheral blood smear
1. Megaloblastosis increases the likelihood of
vitamin B12 or folate deficiency, but can also be seen
in other primary bone marrow disorders.
2. Blasts implicate a possible myelodysplastic
syndrome or acute leukemia.
3. Leukoerythroblastic smear. A
leukoerythroblastic smear, which reveals early
(nucleated) red blood cells (RBCs) and early
white blood cells (WBCs) (i.e., bands,
metamyelocytes, myelocytes), implies marrow
invasion by malignancy (either a solid organ cancer
or a hematologic neoplasm), fibrosis, or infection.
Teardrop cells (i.e., RBCs shaped like a teardrop
from being “squeezed” out of the bone marrow) are
frequently seen with leukoerythroblastosis.
4. Pseudo–Pelger-Huet anomaly (i.e., neutrophils
with bilobed nuclei) is seen in patients with
myelodysplasia (see Chapter 70).

ii. Vitamin B12 and folate levels are often obtained.

iii. HIV test. An HIV test should be performed in patients
with risk factors given its association with a wide array of
hematologic disorders, including pancytopenia

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Pancytopenia

iv. Viral serologies. Assessment for viral exposures often

by quantitative polymerase chain reaction (PCR) testing
for EBV, CMV, and parvovirus B19.
v. PNH workup. PNH results in intravascular hemolysis
that can be precipitated by infections or acidosis (e.g.,
while sleeping at night) resulting in hemosiderinuria;
therefore, PNH should be evaluated in all patients with
pancytopenia, especially those describing episodes of dark
urine. The diagnostic test of choice utilizes flow cytometry
to test for the presence of GPI-anchored proteins, which
are present in normal cells but absent in PNH.

d. Bone marrow biopsy. Because a “dry tap” may occur (i.e.,

one in which bone marrow aspirate is unobtainable as a result
of aplasia, fibrosis, or malignancy), a core marrow biopsy is
essential to determine the etiology of pancytopenia. Patients
with HIV and pancytopenia often still undergo bone marrow
biopsy to rule out a contributing infection or malignancy.
i. Increased cellularity suggests peripheral destruction
(hypersplenism or an immune-mediated disorder) or
inadequate differentiation (acute leukemia and
myelodysplasia). PNH, acute leukemia, and some forms of
myelodysplasia can demonstrate either a hypercellular or
hypocellular marrow.
ii. Decreased cellularity is the common finding in
aplastic anemia, but can also be seen in PNH,
myelodysplasia, and, occasionally, hypoplastic acute
leukemia.
iii. Cytogenetic analysis may help establish the diagnosis
of a myelodysplastic syndrome or acute leukemia by
finding a clonal abnormality and is also used for prognostic
purposes. However, up to half of all acute leukemias may
have a normal karyotype.
iv. Other findings. Metastatic solid organ malignancies
can cause pancytopenia via bone marrow infiltration,
which can be seen on biopsy. Furthermore, bone marrow
samples can be sent for molecular analyses or culture to
evaluate for infectious processes as a cause of
pancytopenia.

E. Treatment
a. General treatment is aimed at preventing complications
associated with a decrease in each cell line.
i. Packed RBC transfusions are usually given to maintain
the hemoglobin above 7 gm/dl in most patients and greater
than 8 gm/dl in older patients or those with known or
suspected coronary artery disease. Younger patients may
tolerate a lower hemoglobin. For each unit of packed RBCs

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Pancytopenia

transfused, the hemoglobin is expected to rise by

approximately 1 g/dL and the hematocrit by 3%.
ii. Platelet transfusions may be necessary to control
bleeding or when the platelet count falls below 10,000
cells/μL to reduce the risk for spontaneous bleeding (see
Chapter 60).
iii. Infection prevention and treatment
1. Granulocyte colony-stimulating factor (G-CSF)
is sometimes used to increase neutrophil counts.
2. Neutropenic precautions (e.g., handwashing and
minimizing exposure to those with infectious
symptoms) should be used for patients at the highest
risk for neutropenia (i.e., neutrophil count <500 cells/
uL).s. Prophylactic antibiotics in the absence of signs
or symptoms of infection are not recommended.
3. Broad-spectrum antibiotics should be used for
patients with fever in the setting of neutropenia,
which is a medical emergency.

b. Specific treatment is aimed at the underlying illness.

Specific treatments for most of the causes of pancytopenia are
found in the relevant chapters. Therapies for PNH and aplastic
anemia will be briefly discussed here.
i. PNH carries approximately a 40% lifetime risk for
thrombosis, and the median survival is 10–15 years.
Approximately 50% of patients with PNH die from either a
thrombotic event or complications of cytopenias.
Spontaneous remission may occur in approximately 15% of
patients.
1. The constant hemolysis and hemosiderinuria/
hematuria can actually result in iron deficiency
that may require iron replacement. Likewise,
folate replacement is recommended in all
patients with chronic hemolysis regardless of
the cause.
2. Chronic anticoagulation therapy is indicated for
all patients who have a history of thrombosis.Patients
with a history of thrombosis should be managed
similarly to other patients with a hypercoagulable
state.
3. Eculizumab is a monoclonal antibody approved by
the Food and Drug Administration (FDA) that binds to
the C5 component of complement and inhibits
complement activation. It has been demonstrated to
reduce the rate of hemolysis, transfusion
requirements, and rate of thrombotic complications in
patients with PNH. Patients receiving eculizumab
require prophylaxis against neisseria.

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Pancytopenia

4. Bone marrow transplantation may be curative

but carries significant morbidity and mortality.
Therefore, it is often only used for late-stage
complications of PNH, including aplastic anemia, or
acute leukemia, or in cases of eculizumab resistant
PNH.

ii. Aplastic anemia

1. Removal of potential etiologies (e.g., offending
medications) is always important.
2. Transfusion support and appropriate antibiotic
therapy for infectious complications is necessary.
3. Pharmacologic therapy. Decisions regarding
therapy are dependent on the severity of the aplastic
anemia as well as the age of the patient.
Pharmacologic therapy is the preferred treatment for
patients who are greater than 40 years of age, or in
younger patients without a sibling-matched donor for
allogeneic stem cell transplantation.
a. Antithymocyte globulin is usually the first-line
pharmacologic treatment for patients with severe
aplastic anemia. Two forms of the antibody exist
(ATGAM, derived from horses, and thymoglobulin,
derived from rabbits).
b. Immunosuppressive agents (e.g.,
cyclosporine) are used in conjunction with
antithymocyte globulin and increase the likelihood
of remission.

4. Bone marrow transplantation may cure 80% of

patients, but morbidity and mortality increase with
patient age and with the use of unrelated allogeneic
donors, compared to transplantation with HLA-
matched, related donors. Because blood product
transfusions may increase risk for graft rejection,
transplant candidates should only receive
transfusions when it is absolutely necessary. When
whole blood or platelet transfusions are required,
they should have the leukocytes removed using a
special filter (a process called “leukoreduction”).
Such “leuko-poor” transfusions decrease the risk for
HLA-antigen immunization and risk for viral
infections. If the patient is neutropenic, irradiating
the blood product may lessen the chance of graft-
versus-host reaction. Transfusions from potential
organ donors should never be given. Matched-related
donor allogeneic hematopoietic stem cell
transplantations are typically considered as first-line
therapy for patients younger than 40 years. For those

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Pancytopenia

older than 40 year, they are considered for use as

second-line or later therapy. For those younger than
40 years without a matched-related donor,
immunosuppressive therapy is the current first-line
treatment option.
5. Spontaneous recovery is uncommon and usually
seen only in mild or moderate cases.

Suggested Further Readings

Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood 2014;124:2804.

McMahon B, Kamath S. Pancytopenia in a patient with hypothyroidism.

JAMA 2016;315:1648–9.

Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood

2012;120:1185.

Townsley DM, Dumitriu B, Liu D, et al. Danazol treatment for telomere

diseases. N Engl J Med 2016;374:1922–31.

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