Assessment of

pancytopenia

Straight to the point of care

Last updated: Sep 10, 2021

 Table of Contents
Overview 3
Summary 3

Theory 4
Aetiology 4

Emergencies 9
Urgent considerations 9

Diagnosis 10
Approach 10
Differentials overview 18
Differentials 21

Guidelines 45

References 46

Images 50

Disclaimer 56
Assessment of pancytopenia Overview

Summary
Pancytopenia is a reduction in the number of red blood cells, white blood cells, and platelets in the peripheral
blood below the lower limits of the age-adjusted normal range for healthy people. It is therefore the

OVERVIEW
combination of anaemia, leukopenia, and thrombocytopenia.

Pancytopenia may result from decreased production of blood cells, resulting from bone marrow failure, or
immune-mediated destruction of blood cells, or non-immune-mediated sequestration in the periphery/spleen.

The diagnosis of pancytopenia is made from the results of an automated full blood count and examination
of the peripheral smear but, as the aetiology of pancytopenia varies significantly, a detailed diagnostic
evaluation is required in every instance.

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
3
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Theory

Aetiology
Pancytopenia may be due to decreased bone marrow cell production or bone marrow failure, clonal disorders
of haematopoiesis, increased non-immune-mediated destruction or sequestration, or an immune-mediated
THEORY

destruction of blood cells.

Table of aetiologies for pancytopenia (SLE: systemic lupus erythematosus, CMV:

cytomegalovirus, EBV: Epstein-Barr virus, GVHD: graft-versus-host disease)
From the collection of Jeff K. Davies

Decreased bone marrow production

The bone marrow is the site of production of red blood cells, white blood cells, and megakaryocytes, from
which platelets arise. Once the cells are made they are released into the peripheral circulation. This process
requires adequate haematopoietic stem cell activity and a functional bone marrow stromal environment. The
high proliferative rate of the marrow requires adequate nutritional status, particularly vitamin B12 and folic
acid, and trace amounts of other elements.

Chemotherapy

• The most common cause of transient pancytopenia in all age groups is cytotoxic chemotherapy
and radiotherapy. Chemotherapy-related pancytopenia rarely presents a diagnostic dilemma,

4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Theory
and usually resolves within 1 to 2 weeks. Of note, some individuals may have known or unknown
proliferative defects or particular pharmacogenetics, which may predispose them to more severe
and longer duration pancytopenia. Some regimens are associated with significantly longer periods of
pancytopenia. Longer than expected post-chemotherapy-related pancytopenia should be investigated.

THEORY
Megaloblastic anaemia

• Although most cases of megaloblastic anaemia cause a macrocytic anaemia without leukopenia or
thrombocytopenia, severe megaloblastic anaemia can result in pancytopenia. Megaloblastic anaemia
most commonly arises from deficiency of vitamin B12 (e.g., pernicious anaemia, an autoimmune
condition where autoantibodies interfere with the function of intrinsic factor, which is required for
absorption of vitamin B12 within the gastrointestinal tract). Less commonly, B12 deficiency is caused
by dietary deficiency (in vegans) or by malabsorption in the gut.
• Folic acid deficiency, almost always dietary in origin, also results in megaloblastic anaemia.

Bone marrow infiltration

• Infiltration of the bone marrow is a common cause of pancytopenia and commonly results from
malignant disease. In general, the infiltrate is cellular and may be of haematological origin (e.g., acute
myeloid and lymphoblastic leukaemia, myeloma, non-Hodgkin's lymphoma, hairy cell leukaemia,
chronic lymphocytic leukaemia, and myelofibrosis) or non-haematological malignancies (e.g., breast,
lung, kidney, prostate, and thyroid). In children, pancytopenia can be caused by neuroblastoma,
rhabdomyosarcoma, Ewing's sarcoma, and retinoblastoma.
Lysosomal storage disorders

• Lysosomal storage disorders (e.g., Gaucher's disease) can infiltrate the marrow, resulting in
pancytopenia. The infiltrate may be largely reticulin fibrosis, which is also associated with malignant
conditions. Gaucher's disease patients may have massive splenomegaly and functional hypersplenism
in addition to infiltration of the bone marrow.
Other causes

• Rarer causes of pancytopenia arising from decreased bone marrow production of blood cells include
anorexia nervosa, transfusion-associated graft-versus-host disease in immunosuppressed patients,
and heavy metal poisoning (e.g., arsenic).[1]
• Infections such as HIV have also been associated with pancytopenia secondary to underproduction
(mostly frequently affecting only red cell production), as has parvovirus in individuals with specific
predisposing conditions (haemolytic anaemia; most prominently sickle cell anaemia and hereditary
spherocytosis).

Clonal disorders of haematopoiesis

Myelodysplastic syndrome (MDS) is a common acquired clonal disorder of haematopoietic cells,
characterised by ineffective and dysplastic haematopoiesis and a propensity for evolution to acute myeloid
leukaemia. In children, the term refractory cytopenias of childhood (RCC) is often used. The bone marrow
may be either hypercellular or hypocellular. In both cases there is commonly peripheral blood pancytopenia.
In addition to decreased or inadequate production of blood cells within the marrow, there is sometimes an
immune-mediated mechanism contributing to the peripheral blood pancytopenia in MDS.

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
5
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Theory
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare (1-2 cases per million general population) acquired
clonal disorder of haematopoietic cells, caused by somatic mutation of the X-linked phosphatidylinositol
glycan A gene and resulting in deficient expression of glycosylphosphatidylinositol-anchored proteins.[2]
PNH is clinically characterised by intravascular haemolysis and thrombosis, and evolution of pancytopenia is
THEORY

common (probably arising from a combination of decreased bone marrow production secondary to acquired
defects in haematopoietic stem cells and cell destruction). There is an overlap in clinical and laboratory
features between PNH patients and those with idiopathic aplastic anaemia (IAA) and even MDS.

Hypoplastic myelodysplastic syndrome with dysplastic normoblasts

Morris Edelman, MD and Peihong Hsu, MD

Bone marrow failure

Congenital and inherited bone marrow failure syndromes (IBMFS) most often present in childhood, although
diagnosis in adulthood is increasing, secondary to awareness and greater testing.

• Fanconi's anaemia is predominantly an autosomal recessive disorder (rare X-linked and dominant
inheritance has been described) in which over 20 dysfunctional proteins result in decreased
haematopoiesis and bone marrow failure.[3] Fanconi's anaemia is variably characterised by short
stature, hyperpigmentation, skeletal anomalies, increased incidence of solid tumours and leukaemia,
and an increased cellular sensitivity to DNA damaging agents.[4] [5] [6]
• Dyskeratosis congenita (DC), inherited as X-linked, autosomal dominant or autosomal recessive
disorder, arises from genetic lesions that compromise telomere integrity, with resulting loss of cell self-
renewal and regeneration.[7] Mutations in 14 genes associated with telomere biology can be identified
in the majority of patients with clinical features of classic DC.[8] [9] [10] Classic DC is defined by nail
dystrophy, mucosal leukoplakia, and skin pigmentation changes, all ranging in severity from virtually
non-existent to severe.[6] Other abnormalities include bone marrow failure, premature balding and
grey hair, urethral strictures, excessive tear production, and pulmonary fibrosis.[11]
• Idiopathic (acquired) aplastic anaemia (IAA) is a rare acquired condition (2-6 cases per million
general population). The diagnosis of IAA requires the presence of pancytopenia in combination

6 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Theory
with decreased bone marrow cellularity without infiltration or fibrosis.[12] IAA is therefore a diagnosis
of exclusion and has to be differentiated carefully from hypocellular MDS as well as congenital and
IBMFS.[13] Some patients have an antecedent history of viral infection, hepatitis, or exposure to
drugs. Severe IAA (where neutropenia and thrombocytopenia are more profound) is a life-threatening

THEORY
condition.
• Other rare inherited single cell cytopenias, such as Diamond-Blackfan anaemia (DBA), Shwachman-
Diamond syndrome (SDS), and amegakaryocytic thrombocytopenia (AMT), may evolve to
pancytopenia.[6]
• Using whole exome and whole genome sequencing, gene mutations seldom reported in inherited bone
marrow failure have been identified in patients with bone marrow failure of suspected inherited origin
but unresolved diagnosis.[14]

Aplastic anaemia: normocellular bone marrow is shown on the left; and empty
marrow, typical of congenital or acquired aplastic anaemia, is shown on the right
Morris Edelman, MD and Peihong Hsu, MD

Increased destruction or sequestration

Most cases of pancytopenia that are accompanied by adequate bone marrow production of blood cells result
from increased sequestration of blood cells within the spleen. Conditions that result in pancytopenia from
functional hypersplenism include:

• Liver disease (with associated portal hypertension) caused by alcoholic liver cirrhosis, chronic hepatitis
B and C infection, autoimmune hepatitis, or idiopathic portal hypertension.
• Myeloproliferative disorders (e.g., chronic myeloid leukaemia may present with massive splenomegaly
resulting in pancytopenia despite adequate production of blood cells within the bone marrow). These
conditions rarely occur in children.
• Acute and chronic infections that result in hypersplenism (e.g., brucellosis and visceral leishmaniasis).
Consideration of exposure and travel history is of particular relevance.
• Haemophagocytic syndromes, a heterogeneous group of disorders characterised by increased
macrophage or histiocyte activity within the bone marrow and other organs. Hepatomegaly and
splenomegaly are common clinical features. Haemophagocytic syndromes may be categorised as
primary (where the haemophagocytic syndrome dominates the clinical features of the condition, as
in primary haemophagocytic lymphohistiocytosis [pHLH]), which are usually genetic in origin, or may
be reactive to systemic conditions with a range of other clinical features (e.g., autoimmune disorders,
T-cell lymphoma, often referred to as macrophage activation syndrome). These distinctions may

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
7
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Theory
be difficult to discern in some instances, but genetic testing is available for a number of the genes
implicated in pHLH.

Immune-mediated destruction of blood cells

THEORY

Drug-induced immune pancytopenia arises when antibodies with cross-reactivity for drug and haematopoietic
cells are generated. This is associated most frequently with quinine, sulfonamides, and rifampicin.

Immune pancytopenia may be seen in up to 20% of patients with Evans syndrome (classically the
combination of autoimmune thrombocytopenia and haemolytic anaemia), which is seen more commonly
in children than in adults.[15] A significant number of people with Evans syndrome have underlying
autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder resulting from mutations that
inhibit apoptosis in the regulation of the immune response. Mild cases have been reported, suggesting that
the incidence is significantly understated. ALPS is characterised by a usually benign lymphoproliferation
(lymphadenopathy and splenomegaly) and autoimmunity, most often directed towards cells of the myeloid
lineage (erythrocytes, granulocytes, and platelets),[16] although other targets are less commonly involved
(e.g., autoimmune hepatitis).

Combination pancytopenia
Many conditions associated with pancytopenia result from a combination of decreased bone marrow
production and increased destruction or sequestration of blood cells. They include:

• Connective tissue disorders (most commonly rheumatoid arthritis and systemic lupus erythematosus)
• Acute cytomegalovirus infection
• Mycobacterial infection
• Infectious mononucleosis
• HIV
• Felty syndrome (rheumatoid arthritis, splenomegaly, and neutropenia).

8 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Emergencies

Urgent considerations
(See Differentials for more details)

Unless the underlying cause is already apparent (and being appropriately managed), the presence of
pancytopenia always warrants investigation by a haematologist.

Severe pancytopenia
In all cases of severe pancytopenia (symptomatic anaemia, WBC <0.5 x 10⁹/L [<500/microlitre], and platelets
<20 x 10⁹/L [<20 x 10³/microlitre]), investigation is mandatory within 24 to 48 hours. Supportive therapy with
red blood cell and platelet transfusion, and broad-spectrum antibiotics to treat anaemia, bleeding, and/or
infection may need to be initiated before the underlying cause has been ascertained.

Acute myeloid leukaemia

Occurs in all age groups but predominantly in older adults. Cytogenetic abnormalities are prognostically

EMERGENCIES
important and affect patient management. Clinical history plus most signs and symptoms usually reflect bone
marrow failure. These include fatigue, dyspnoea, dizziness, bleeding, easy bruising, and recurrent infections.
Most patients are treated with chemotherapy induction and consolidation regimens. Haematopoietic stem cell
transplantation is also beneficial in select patients.

Acute lymphoblastic leukaemia

This is the most common acute leukaemia in childhood, but also occurs in adults. Clinical history plus
most signs and symptoms usually reflect blood marrow failure. These include fatigue, dyspnoea, dizziness,
bleeding, easy bruising, and recurrent infections. Physical examination may reveal pallor and ecchymoses,
and lymphadenopathy. Neurological symptoms and/or signs may occur if central nervous system involvement
is present. Treatment uses multi-agent dose-intense chemotherapy regimens in induction, consolidation, and
maintenance phases.

Acquired aplastic anaemia

This rare condition affecting all age groups is characterised by pancytopenia with reduced or absent
haematopoiesis in the bone marrow in the absence of a malignant infiltrate or fibrosis. Severe aplastic
anaemia (SAA) is defined, using the modified Camitta criteria, as having a marrow cellularity <25% with at
least 2 of the 3 following criteria:[17] [18] [19]

• neutrophils <0.5 x 10⁹/L (<500/microlitre) (very severe aplastic anaemia [VSAA] <0.2 x 10⁹/L [<200/
microlitre])
• platelets <20 x 10⁹/L (<20 x 10³/microlitre)
• reticulocyte count <20 x 10⁹/L (<20 x 10³/microlitre).

Clinical history plus most signs and symptoms usually reflect bone marrow failure. These include fatigue,
dyspnoea, dizziness, bleeding, easy bruising, and recurrent infections.

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
9
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Approach
Unless the underlying cause is already apparent (and being appropriately managed), the presence of
pancytopenia always warrants investigation by a haematologist.

The presence of severe pancytopenia (symptomatic anaemia, WBC <0.5 x 10⁹/L [<500/microlitre], and
platelets <20 x 10⁹/L [<20 x 10³/microlitre]) calls for urgent investigation (within 24-48 hours). A thorough
history and physical examination are always required, preferably conducted by a haematologist. A full blood
count and examination of peripheral blood film by a haematologist are essential. Bone marrow examination
by aspirate and biopsy is almost always required.[20] [21] [22]
DIAGNOSIS

Flow diagram for evaluation of pancytopenia. Abbreviations: PNH, paroxysmal

nocturnal haemoglobinuria; IBMFS, inherited bone marrow failure syndromes
From the collection of Jeff K. Davies

History
The causes of pancytopenia are diverse, and likely causes of pancytopenia differ in children and adults.
Particular attention must be paid to patient and family history. Of significance is any history of previous
pancytopenia, or single cell cytopenia, aplastic anaemia, inherited bone marrow failure syndromes (IBMFS),
early fetal loss, history of cancer, metabolic disorders, liver disease, or connective tissue disorders. A
thorough drug history is essential.

The symptoms and signs of pancytopenia relate to the blood cell lineages affected (red blood cells, white
blood cells, and platelets). Mild pancytopenia is often symptomless and detected incidentally when a full
blood count is performed for another reason, particularly in association with non-specific viral illnesses in
children. Pancytopenia of this aetiology will recover spontaneously.

10 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis
Spontaneous mucosal bleeding (gums, gastrointestinal tract), petechiae, and purpura with easy bruising
secondary to thrombocytopenia are usually the first symptoms to develop directly related to more severe
pancytopenia. This is often followed by symptomatic anaemia (fatigue, shortness of breath, dependent
oedema, chest pain in patients with ischaemic disease) and bacterial infection secondary to neutropenia
(fever, mucositis, abscesses, rigors).

Physical examination
A thorough physical examination is required, preferably by a haematologist. Weight loss and/or anorexia
are harbingers of underlying infection (either precedent to the pancytopenia or as a result of it) or
malignancy. Spontaneous mucosal bleeding (gums, gastrointestinal tract), petechiae, and purpura with
easy bruising secondary to thrombocytopenia are usually the first signs to develop directly related to more
severe pancytopenia. These signs are often accompanied by lymphadenopathy (underlying infection,
mononucleosis, lymphoproliferative disorder, and malignancy). Abdominal discomfort is a common
presentation of splenomegaly and associated conditions. Widespread bone pain and loss of height suggest
myeloma, joint pain suggests systemic lupus erythematosus (SLE), and sore throat consideration of
mononucleosis.

The following reference points to specific organ systems and associated conditions may be helpful to guide
the examination.

Eye examination

• Retinal haemorrhage (thrombocytopenia)

• Leukaemic infiltrates (acute leukaemia)
• Jaundiced sclera (paroxysmal nocturnal haemoglobinuria [PNH], hepatitis, cirrhosis)
• Epiphora (dyskeratosis congenita)

DIAGNOSIS

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
11
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Icterus or jaundice
CDC. Dr Thomas F. Sellers/Emory University; used with permission

Oral examination

• Oral petechiae or haemorrhage (thrombocytopenia)

• Stomatitis or cheilitis (neutropenia, vitamin B12 deficiency)
• Gingival hyperplasia (leukaemia)
DIAGNOSIS

• Oral candidiasis or pharyngeal exudate (neutropenia, herpes family virus infections)

Angular cheilitis
From the collection of Dr Wanda C. Gonsalves; patient consent obtained

12 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Gingival enlargement, petechiae and bleeding in acute myeloid leukaemia

Collection of Giuseppina Campisi, DDS, MS and Giuseppe Pizzo, DDS

Cardiovascular examination

• Tachycardia, oedema, congestive cardiac failure (all signs of symptomatic anaemia)

• Evidence of prior cardiac surgery (cardiac disease associated with congenital syndromes)

DIAGNOSIS
Respiratory examination

• Clubbing (lung cancer)

• Tachypnoea (sign of symptomatic anaemia)

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
13
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Clubbing of nails showing loss of the classic Lovibond's angle

From the collection of Dr Murlidhar Rajagopalan

Abdominal examination

• Right upper quadrant tenderness (hepatitis)

• Lymphadenopathy (infection, lymphoproliferative disorder, HIV disease)
• Signs of chronic liver disease
• Splenomegaly (infection, myeloproliferative and lymphoproliferative disorders)
Skin examination

• Malar rash (SLE)

• Purpura/bruising (thrombocytopenia)
DIAGNOSIS

• Reticular pigmentation, dysplastic nails (dyskeratosis congenita)

• Hypopigmented areas
• Hyperpigmentation, café au lait (Fanconi's anaemia)

14 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Café au lait spots on the back of a young boy

From the personal collection of Dr Vincent M. Riccardi; used with permission

Musculoskeletal examination

• Short stature (Fanconi's anaemia, other congenital syndromes)

• Swelling/synovitis (SLE)

DIAGNOSIS
• Abnormal thumbs (e.g., Fanconi's anaemia)

Signs associated with HIV disease

• Morbilliform rash early

• Kaposi's sarcoma, ulcerating nodules later

Inherited bone marrow failure syndromes (IBMFS) may have characteristic bony, renal, and other congenital
abnormalities, or pulmonary or cutaneous abnormalities. A search for these should not be part of an initial
work-up but, if found on images obtained for other reasons, should prompt further consideration of IBMFS as
the aetiology of pancytopenia. The absence of physical anomalies does not rule out an IBMFS.

Laboratory
A full blood count and examination of peripheral blood film by a haematologist are essential. A standard
battery of evaluative tests may include:

• Serum reticulocyte count

• Serum liver function tests and hepatic serology
• Serum coagulation profile, bleeding time, fibrinogen, and D-dimer

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
15
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis
• Serum direct antiglobulin test
• Serum B12 and folate
• Serum HIV and nucleic acid testing.

Specific testing pinpoints diagnosis in the following conditions:

• Fanconi's anaemia: diepoxybutane (DEB) test for chromosomal breakage in peripheral blood
lymphocytes
• Lymphoproliferative disorders: immunophenotyping, cytogenetics, lymph node biopsy
• Multiple myeloma: immunoelectrophoresis
• Paroxysmal nocturnal haemoglobinuria (PNH): peripheral blood immunophenotyping for deficiency of
phosphatidylinositol-glycan-linked molecules on peripheral blood cells (e.g., CD16, CD55, CD59)
• Cytomegalovirus infection: serum IgM and IgG
• Epstein-Barr: serum monospot, viral capsid antigen (VCA), and Epstein-Barr nuclear antibody (EBNA)
• Leishmaniasis and other rare infections: blood and bone marrow culture, serum enzyme-linked
immunosorbent assay (ELISA)
• Rare genetic and metabolic disease: leukocyte glucocerebrosidase activity.

Further specific tests include:

• Serum prostate-specific antigen in suspect cases of prostatic malignancy

• Telomere length
• Genetic analysis involving tests for individual disorders based upon clinical suspicion, or newer panels
(many currently in development) to evaluate for mutations and deletions. Germline mutations may
be absent in peripheral blood lymphocytes due to mosaicism; consider skin fibroblasts for genetic
analysis if there is a strong suspicion of a germline mutation.[23] Genetic testing, now feasible and
more accessible, is replacing some of the more cumbersome screening tests.
Examination of bone marrow is almost always indicated in cases of pancytopenia unless the cause is
otherwise apparent (e.g., established liver disease with portal hypertension). The bone marrow examination
consists of both an aspirate and a trephine biopsy, which yield complementary information in this setting.
The differential diagnosis of pancytopenia may be broadly classified based on the bone marrow cellularity
DIAGNOSIS

(reduced cellularity indicates decreased production of blood cells, whereas normal/increased cellularity
indicates ineffective production or increased destruction or sequestration of blood cells).

Specifically, bone marrow aspirate permits examination of:

• Cytology (megaloblastic change, dysplastic changes, abnormal cell infiltrates, haemophagocytosis,

and infection [e.g., Leishman-Donovan bodies])
• Immunophenotype (acute and chronic leukaemias, lymphoproliferative disorders)
• Cytogenetics (myelodysplasia [MDS], acute and chronic leukaemias, lymphoproliferative disorders).

Bone marrow trephine biopsy permits specific examination of cellularity:

• Normal or increased in MDS, acute and chronic leukaemia, myeloma with plasma cells,
carcinomatosis marrow infiltration, peripheral destruction/sequestration conditions, early HIV disease,
and megaloblastic anaemia
• Decreased after chemotherapy, acute infection/sepsis, advanced HIV disease, hypoplastic
myelodysplastic syndrome, congenital/inherited BMFS, idiopathic aplastic anaemia, SLE, and PNH.
Trephine biopsy also permits examination of histology and evaluation for:

16 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

• Cellular infiltration
• Blasts
• Features of MDS (e.g., abnormal localisation of immature precursors)
• Reticulin stain (fibrosis).
In the developed world, it has been proposed that the most likely aetiology of new onset pancytopenia,
when investigated with bone marrow evaluation, is acute lymphoblastic leukaemia in children and acute
myeloid leukaemia/myelodysplastic syndrome in adults.[24] In some other parts of the world (e.g., India),
hypersplenism and infection may be the most frequent aetiologies of pancytopenia.[25]

Radiology
Abdominal ultrasound scan or computed tomography scan of the abdomen is indicated to evaluate for
splenomegaly. Chest radiograph may reveal tumour masses responsible for pancytopenia (e.g., carcinoma,
thymoma). In cases where metastatic infiltration of the bone marrow is suspected, thyroid ultrasound or
breast imaging may also be appropriate. Inherited bone marrow failure syndromes may have characteristic
bony, renal, or pulmonary abnormalities. A search for these should not be part of an initial work-up but, if
found on images obtained for other reasons, should prompt further consideration of IBMFS as the aetiology
of pancytopenia.

DIAGNOSIS

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
17
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Differentials overview

Common

Chemotherapy

Radiotherapy

Vitamin B12 deficiency

Folic acid deficiency

Bone marrow infiltration by non-haematological malignancy

Non-Hodgkin's lymphoma

Hairy cell leukaemia

Chronic lymphocytic leukaemia

Myelodysplasia

Cirrhosis

Seronegative (idiopathic) hepatitis (likely autoimmune)

Hepatitis B
DIAGNOSIS

Hepatitis C

Autoimmune hepatitis

HIV

Cytomegalovirus infection

Mycobacterial infection

Uncommon

Acute myeloid leukaemia

Acute lymphocytic leukaemia (ALL)

Multiple myeloma

18 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Uncommon

Myelofibrosis

Lysosomal storage disorders

Anorexia nervosa

Graft-versus-host disease (GVHD)

Heavy metal (arsenic) poisoning

Parvovirus infection in sickle cell anaemia (and other haemolytic anaemias)

Dyskeratosis congenita (DC)

Paroxysmal nocturnal haemoglobinuria (PNH)

Idiopathic aplastic anaemia

Fanconi's anaemia

Other rare inherited cytopenias (e.g., Diamond-Blackfan anaemia, Shwachman-Diamond syndrome,

amegakaryocytic thrombocytopenia)

Idiopathic portal hypertension

Chronic myeloid leukaemia

DIAGNOSIS
Brucellosis

Leishmaniasis

Haemophagocytosis syndromes

Drug-induced immune pancytopenia

Evans syndrome with associated neutropenia

Autoimmune lymphoproliferative syndrome (ALPS)

Systemic lupus erythematosus

Rheumatoid arthritis

Infectious mononucleosis

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
19
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Uncommon

Felty syndrome
DIAGNOSIS

20 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Differentials

Common

◊ Chemotherapy

History Exam 1st Test Other tests

transient pancytopenia nausea and vomiting, »peripheral blood: »bone marrow

associated with hair loss, easy bruising, irregular size and aspirate: variable
chemotherapeutic bleeding, pallor, fever, shape of red blood hypoplasia
agents rigors cells (anisocytosis Order if extended delay
and poikilocytosis), in recovery (which may
basophilic stippling
suggest a relapse).

»bone marrow
biopsy: hypoplasia,
megaloblastosis
Order if extended delay
in recovery (which may
suggest a relapse).

◊ Radiotherapy

History Exam 1st Test Other tests

transient pancytopenia nausea and vomiting, »peripheral blood: »bone marrow

associated with hair loss, easy bruising, irregular size and aspirate: variable
radiotherapy bleeding, pallor, fever, shape of red blood hypoplasia
rigors cells (anisocytosis Order if extended delay
and poikilocytosis), in recovery (which may

DIAGNOSIS
basophilic stippling
suggest a relapse).

»bone marrow
biopsy: hypoplasia,
megaloblastosis
Order if extended delay
in recovery (which may
suggest a relapse).

◊ Vitamin B12 deficiency

History Exam 1st Test Other tests

may be a history of glossitis and »peripheral blood »intrinsic factor

autoimmune disorders, angular stomatitis, film: oval macrocytic antibody: may
vegan diet, total or easy bruising or red blood cells be positive order if
partial gastrectomy, spontaneous bleeding (RBCs), irregular pernicious anaemia is
ileal resection, or (rare), peripheral size and shape of suspected
RBCs (anisocytosis

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
21
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Common

◊ Vitamin B12 deficiency

History Exam 1st Test Other tests

coeliac disease; sensory loss, balance and poikilocytosis),
gradual onset of fatigue and gait disturbance hypersegmented
granulocytes (>5 lobes)
RBC mean volume
usually normal at
presentation due to
gross anisocytosis.

»serum reticulocyte
count: usually low
»serum B12: low in
B12 deficiency
»bone marrow
aspirate: hypercellular,
megaloblastic
erythroblasts, giant
metamyelocytes
»serum LDH:
moderately raised
»serum bilirubin:
moderately raised,
mostly indirect

◊ Folic acid deficiency

History Exam 1st Test Other tests

DIAGNOSIS

may be a history of glossitis and »peripheral blood

diet poor in green angular stomatitis, film: oval macrocytic
vegetables, ileal easy bruising or red blood cells
resection, pregnancy spontaneous bleeding (RBCs), irregular
with hyperemesis; (rare), peripheral size and shape of
gradual onset of fatigue sensory loss, balance RBCs (anisocytosis
and gait disturbance and poikilocytosis),
hypersegmented
granulocytes (>5 lobes)
RBC mean volume
usually normal at
presentation due to
gross anisocytosis.

»serum reticulocyte
count: usually low
»serum RBC folate:
low in folate deficiency

22 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Common

◊ Folic acid deficiency

History Exam 1st Test Other tests

»bone marrow
aspirate: hypercellular,
megaloblastic
erythroblasts, giant
metamyelocytes
»serum LDH:
moderately raised
»serum bilirubin:
moderately raised,
mostly indirect

Bone marrow infiltration by non-haematological malignancy

History Exam 1st Test Other tests

may be a history cachexia, finger »peripheral »CT of abdomen:

of breast, prostate, clubbing, breast lump, blood film: leuko- may reveal abdominal
lung, thyroid, kidney, lymphadenopathy, erythroblastic cell forms or renal mass
gastrointestinal enlarged irregular »bone marrow »serum prostatic-
malignancy or prostate, abdominal aspirate: clumps of specific antigen:
metastatic melanoma in mass tumour cells elevated in prostate
adults; neuroblastoma,
Aspirate may be dry cancer
rhabdomyosarcoma,
Ewing's sarcoma, (non-diagnostic) or »thyroid ultrasound:
retinoblastoma in normal when infiltration irregular mass or
children; weight loss, nodule
is detectable on the
anorexia, fatigue »breast imaging:
trephine roll or trephine

DIAGNOSIS
mass or calcifications
biopsy.[26]

»chest x-ray: mass

(lung cancer)
»serum liver
function tests:
elevated alanine
aminotransferase
and aspartate
aminotransferase
(hepatic metastases)
»serum coagulation
profile: prolonged
prothrombin time and
partial thromboplastin
time
»serum fibrinogen
and D-dimer:
diminished fibrinogen
and elevated D-

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
23
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Common

Bone marrow infiltration by non-haematological malignancy

History Exam 1st Test Other tests

dimer (indicative of
chronic disseminated
intravascular
coagulation)
Common in
mucin-secreting
adenocarcinoma (e.g.,
prostate).

Non-Hodgkin's lymphoma

History Exam 1st Test Other tests

gradual onset of cachexia, »peripheral blood

fatigue, weight loss, lymphadenopathy, film: variable; may
lymphadenopathy, hepatosplenomegaly show circulating
fever, rigors, respiratory lymphoma cells
distress, abdominal »bone marrow
distention aspirate: increased
proportion of lymphoid
cells
»immunophenotyping
(of peripheral blood
or bone marrow):
clonal population of
lymphoid cells
DIAGNOSIS

»lymph node biopsy:

lymphoproliferative
disorder

Hairy cell leukaemia

History Exam 1st Test Other tests

gradual onset of cachexia, »peripheral blood

fatigue, weight loss, lymphadenopathy, film: presence of hairy
lymphadenopathy, hepatosplenomegaly cells
fever, rigors, respiratory Absent monocytes
distress, abdominal suggests hairy cell
distention
leukaemia, circulating
lymphoid cells may
have characteristic
morphology.[29]

24 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Common

Hairy cell leukaemia

History Exam 1st Test Other tests

»bone marrow
aspirate: increased
proportion of lymphoid
cells
»immunophenotyping
(of peripheral blood
or bone marrow):
clonal population of
lymphoid cells

Chronic lymphocytic leukaemia

History Exam 1st Test Other tests

gradual onset of cachexia, »peripheral blood »lymph node biopsy:

fatigue, weight loss, lymphadenopathy, film: circulating lymphoproliferative
lymphadenopathy, hepatosplenomegaly leukaemia cells disorder
fever, rigors, respiratory »bone marrow
distress, abdominal aspirate: increased
distention proportion of lymphoid
cells
»immunophenotyping
(of peripheral blood
or bone marrow):
clonal population of
lymphoid cells

DIAGNOSIS
Myelodysplasia

History Exam 1st Test Other tests

incidental presentation pallor, oedema, »peripheral blood »cytogenetics: may

common, gradual onset purpura, or petechiae film: may have be abnormal
of fatigue, shortness irregular or macrocytic Cytogenetic
of breath, recurrent red blood cells, abnormalities can be
infection, easy bruising, dysplastic granulocytes,
spontaneous mucosal platelets may be large detected in 40% to 70%
bleeding, abdominal and hypogranular of de novo MDS cases,
fullness and 95% of secondary
»serum reticulocyte
count: usually low, MDS cases.[30]
may be normal or
raised
»bone marrow
aspirate: usually
hypercellular,
rarely, hypocellular

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
25
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Common

Myelodysplasia

History Exam 1st Test Other tests

(hypocellular
myelodysplasia [MDS]),
dysplastic changes

◊ Cirrhosis

History Exam 1st Test Other tests

liver disease secondary pallor, jaundiced »peripheral »bone marrow

to viral, autoimmune, or sclerae, abdominal blood film: aspirate: hypercellular,
alcoholic hepatitis distension, ascites, macrocytes, target erythroid hyperplasia
hepatosplenomegaly cells, stomatocytes,
acanthocytes
»reticulocyte count:
elevated or normal
»serum liver
function tests: may
be elevated

◊ Seronegative (idiopathic) hepatitis (likely autoimmune)

History Exam 1st Test Other tests

no antecedent history pallor, jaundice »peripheral »bone marrow

blood film: aspirate: hypercellular,
macrocytes, target erythroid hyperplasia
DIAGNOSIS

cells, stomatocytes,
acanthocytes
»reticulocyte count:
elevated or normal
»serum liver
function tests:
elevated
»viral hepatitis
serology: no evidence
of past or current
infection

◊ Hepatitis B

History Exam 1st Test Other tests

key risk factors include pallor, jaundice, »peripheral »bone marrow

living in/travel to abdominal blood film: aspirate: hypercellular,
an endemic region, macrocytes, target erythroid hyperplasia
intravenous drug

26 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Common

◊ Hepatitis B

History Exam 1st Test Other tests

use, multiple sexual pain, ascites, cells, stomatocytes,
partners, men who hepatosplenomegaly acanthocytes
have sex with men, »reticulocyte count:
family history of elevated or normal
hepatitis B infection
or hepatocellular »serum liver
carcinoma, household function tests:
contact with an infected elevated
individual, incarceration »serum hepatitis
B surface antigen
(HBsAg): positive

◊ Hepatitis C

History Exam 1st Test Other tests

intravenous drug use pallor, jaundice, ascites, »peripheral »bone marrow

or transfusion, fatigue, spider haemangiomata blood film: aspirate: hypercellular,
myalgia, arthralgia macrocytes, target erythroid hyperplasia
cells, stomatocytes,
acanthocytes
»reticulocyte count:
elevated or normal
»serum liver
function tests:
normal or elevated
»serum hepatitis

DIAGNOSIS
C virus (HCV)
antibody: positive

◊ Autoimmune hepatitis

History Exam 1st Test Other tests

fatigue, malaise, pallor, jaundice, ascites, »peripheral »bone marrow

anorexia, nausea, hepatosplenomegaly, blood film: aspirate: hypercellular,
pruritus encephalopathy macrocytes, target erythroid hyperplasia
cells, stomatocytes,
acanthocytes
»reticulocyte count:
elevated or normal
»serum liver
function tests:
elevated
»autoantibody
screen: positive

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
27
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Common

◊ HIV

History Exam 1st Test Other tests

HIV disease or risk cachexia, generalised »peripheral blood »protein

factors, influenza- lymphadenopathy, film: atypical electrophoresis:
like illness (acute HIV-associated skin lymphocytes (acute polyclonal
seroconversion), lesions (oral hairy seroconversion), hypergammaglobulinaemia
fatigue, easy bruising, leukoplakia, molluscum rouleaux, dysplastic
spontaneous bleeding, contagiosum, Kaposi's neutrophils
fever, rigors (chronic sarcoma) »reticulocyte count:
HIV disease) reduced
»HIV serology:
positive
»bone marrow
aspirate: hypercellular
(acute seroconversion),
hypocellular,
dyserythropoiesis

◊ Cytomegalovirus infection

History Exam 1st Test Other tests

fever, malaise, fever, generalised »peripheral blood

arthralgia, tender tender film: atypical
lymphadenopathy, lymphadenopathy, lymphocytes,
pharyngitis pharyngeal exudates, spherocytes if co-
mild splenomegaly, existing haemolysis
abdominal tenderness »cytomegalovirus-
DIAGNOSIS

specific IgM and

IgG: positive
»bone marrow
aspirate: cellularity
usually increased,
haemophagocytosis
may be prominent
»bone marrow
trephine biopsy:
cellularity usually
increased

◊ Mycobacterial infection

History Exam 1st Test Other tests

HIV disease or cachexia, »peripheral blood

other chronic lymphadenopathy film: rouleaux
immunosuppression, »reticulocyte count:
reduced

28 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Common

◊ Mycobacterial infection

History Exam 1st Test Other tests

fever, weight loss, skin »bone marrow
lesions, cough aspirate:
reduced cellularity,
haemophagocytosis
»bone marrow
trephine biopsy:
reduced cellularity,
granulomas, fibrosis
»bone marrow
culture: positive for
organism

Uncommon

Acute myeloid leukaemia

History Exam 1st Test Other tests

more common in older lymphadenopathy, »peripheral blood

adults (but could be hepatosplenomegaly, film: blasts on blood
any age); rapid onset mucosal bleeding film, presence of Auer's
of fatigue, shortness of rods
breath, fever, rigors »serum prothrombin
time (PT), partial
thromboplastin time
(PTT), fibrinogen,

DIAGNOSIS
D-dimer: may be
abnormal; suspect
disseminated
intravascular
coagulation
»bone marrow
aspiration: usually
hypercellular with
blasts, rarely
hypocellular
Acute promyelocytic
leukaemia most
commonly presents
with pancytopenia.[27]

Diagnosis of acute
leukaemia can be
made with less than
20% blasts in the
bone marrow in

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
29
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Uncommon

Acute myeloid leukaemia

History Exam 1st Test Other tests

erythroleukaemia or
when a characteristic
chromosomal
abnormality is
detected.[28] Rarely,
the bone marrow
may be hypocellular.
Immunophenotyping is
essential to differentiate
hypoplastic acute
leukaemia from aplastic
anaemia.

»bone marrow
biopsy: presence
of blasts, infiltration,
Auer's rods
»immunophenotyping:
detection of clonal
population of blasts
»cytogenetics:
identification or non-
random chromosomal
abnormalities
DIAGNOSIS

Acute lymphocytic leukaemia (ALL)

History Exam 1st Test Other tests

rapid onset of fatigue, fever, »peripheral blood »immunophenotyping

shortness of breath, lymphadenopathy, film: blasts may or may (of peripheral blood
fever, rigors hepatosplenomegaly, not be present or bone marrow):
gum infiltration, detection of clonal
»bone marrow
pallor, petechiae, population of blasts
aspirate: hypercellular
purpura; papilloedema, with blasts; »cytogenetics:
nuchal rigidity, and occasionally identification of non-
meningismus hypocellular (childhood random chromosomal
ALL) abnormalities

30 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Uncommon

Multiple myeloma

History Exam 1st Test Other tests

gradual onset of pallor, vertebral »peripheral blood »radiological

fatigue, weight loss, collapse; less film: rouleaux, skeletal survey:
fever, rigors, back pain, commonly circulating plasma cells lytic lesions and/or
constipation (due to hyperviscosity may rarely be present osteopenia
hypercalcaemia), bone syndrome (purpura, »bone marrow
pain visual defects, aspirate: plasma cell
confusion, neuropathy) infiltrate, abnormal
plasma cells,
plasmablasts
»immunophenotyping
(of peripheral blood
or bone marrow):
plasma cells exhibit
restriction of kappa
or lambda light chain
expression
»serum and urine
electrophoresis:
monoclonal serum
protein and urinary
Bence Jones proteins
(light chains) detected

Myelofibrosis

History Exam 1st Test Other tests

DIAGNOSIS
gradual onset of cachexia, pallor, »peripheral »serum and red
fatigue, weight loss, splenomegaly, blood film: leuko- blood cell folate:
fever, night sweats, hepatomegaly erythroblastic, teardrop- usually diminished
left upper quadrant shaped red blood cells »serum B12: usually
discomfort »bone marrow elevated
aspirate: hypercellular
and fibrotic, often dry
tap and non-diagnostic

◊ Lysosomal storage disorders

History Exam 1st Test Other tests

gradual onset of pallor, splenomegaly or »leukocyte »bleeding time:

fatigue, fever, rigors, hepatosplenomegaly, glucocerebrosidase prolonged
bone pain, abdominal purpura and petechiae activity: reduced or
discomfort, fractures, absent
spontaneous bruising, »peripheral blood
or mucosal bleeding film: pancytopenia

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
31
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Uncommon

◊ Lysosomal storage disorders

History Exam 1st Test Other tests

»reticulocyte count:
may be high, normal, or
reduced
»bone marrow
aspirate: may reveal
Gaucher's cells

◊ Anorexia nervosa

History Exam 1st Test Other tests

may be a prior decreased body »peripheral

history of eating mass index, parotid blood film: red
disorder, distorted swelling, lanugo cell acanthocytes,
body image and self- hair, bradycardia, poikilocytosis and
harming behaviour, hypotension basophilic stippling
amenorrhoea »reticulocyte count:
low
»bone marrow
aspirate:
hypocellular, reduced
haematopoietic cells,
may show gelatinous
transformation
»bone marrow
trephine biopsy:
DIAGNOSIS

hypocellular without
infiltration or fibrosis
»diepox ybutane test:
normal

Graft-versus-host disease (GVHD)

History Exam 1st Test Other tests

non-irradiated cellular rash (particularly hands »peripheral blood

product transfusion in and feet), jaundice, film: no specific
immunocompromised pallor, purpura, features
patient, fatigue, petechiae »reticulocyte count:
spontaneous bruising low
and/or mucosal
bleeding, fever, »bone marrow
diarrhoea aspirate:
hypocellular, reduced
haematopoietic
cells, increased

32 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Uncommon

Graft-versus-host disease (GVHD)

History Exam 1st Test Other tests

macrophages,
erythrophagocytosis
»bone marrow
trephine biopsy:
hypocellular without
infiltration or
fibrosis, increased
macrophages
»skin, liver, upper
gastrointestinal
biopsy: characteristic
appearances of acute
GVHD
»HLA typing of
peripheral blood
lymphocytes:
chimerism
Definitive diagnostic
test.

◊ Heavy metal (arsenic) poisoning

History Exam 1st Test Other tests

environmental pallor, jaundice, signs »peripheral blood

exposure (wood, of portal hypertension film: basophilic

DIAGNOSIS
glass production, may be present stippling
semiconductor industry, »bone marrow
smelting, pesticides), aspirate: hypocellular
headaches, abdominal without infiltrate or
pain fibrosis, decreased
haematopoietic cells,
dyserythropoiesis
»bone marrow
trephine biopsy:
hypocellular without
infiltration or fibrosis
dyserythropoiesis
»diepox ybutane test:
normal
»screening for
parox ysmal
nocturnal
haemoglobinuria
clone: negative

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
33
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Uncommon

◊ Heavy metal (arsenic) poisoning

History Exam 1st Test Other tests

»arsenic level
(serum, urine, hair,
nails): elevated
Serum and urine levels
only indicative of recent
exposure. Hair/nail
arsenic levels indicative
of exposure over prior 6
to 9 months.

◊ Parvovirus infection in sickle cell anaemia (and other

haemolytic anaemias)

History Exam 1st Test Other tests

weakness, and pallor, rash »FBC: drop in

lethargy secondary haemoglobin
to associated aplastic concentration of >30
crisis percent secondary
to complete arrest of
erythropoiesis
»reticulocyte
count: decrease or
absence of measurable
reticulocytes
DIAGNOSIS

»bone marrow
biopsy: remarkable for
severe aplasia

◊ Dyskeratosis congenita (DC)

History Exam 1st Test Other tests

presents in the third or nail and skin atrophy, »peripheral blood »genetic studies:
fourth decade of life, blocked tear ducts, film: red cells usually may identify 1 of
fatigue, spontaneous urethral meatal macrocytic several genetic
bruising and mucosal stenosis, reticulated mutations
»reticulocyte count:
bleeding, fever, rigors skin pigmentation, Dyskeratosis congenita
low or absent
(less common), chronic pallor, purpura, is genetically
tearing, difficulty with petechiae »bone marrow
urination aspirate: heterogeneous and
hypocellular, reduced in some cases the
haematopoietic cells, genetic lesion has
dyserythropoiesis
not been identified.
common
Aplasia only occurs in

34 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Uncommon

◊ Dyskeratosis congenita (DC)

History Exam 1st Test Other tests

»bone marrow X-linked and autosomal
trephine biopsy: recessive forms of DC.
hypocellular without
infiltration or fibrosis In kindreds where the
genetic lesion is known,
»diepox ybutane
test: normal (peripheral screening of potential
blood lymphocytes) related haematopoietic
»screening for stem cell donors is
parox ysmal useful.[13]
nocturnal
haemoglobinuria »telomere length:
(PNH) clone: may be abnormally short;
present length in lymphocytes
Presence of a PNH and granulocytes <1
clone is established percentile for age
by demonstration
of glycosyl
phosphatidylinositol
(GPI)-linked protein
deficiencies on
red blood cell and
neutrophil surfaces by
multiparameter flow
cytometry.[31]

»peripheral blood

DIAGNOSIS
and/or bone marrow
immunophenotyping:
normal
»blood and/or
bone marrow
cytogenetics: clonal
abnormalities present in
some patients

◊ Parox ysmal nocturnal haemoglobinuria (PNH)

History Exam 1st Test Other tests

previous venous pallor, jaundice, portal »peripheral blood »diepox ybutane test:
thrombosis, fatigue, hypertension film: polychromasia normal
intermittent abdominal »reticulocyte count: »screening for PNH
pain and dark urine, relative reticulocytosis clone: positive
blood in stool
»bone marrow Presence of a PNH
aspirate: clone is established
hypocellular, reduced

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
35
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Uncommon

◊ Parox ysmal nocturnal haemoglobinuria (PNH)

History Exam 1st Test Other tests

haematopoietic cells, by demonstration
mast cells may be of glycosyl
increased
phosphatidylinositol
(GPI)-linked protein
deficiencies on
red blood cell and
neutrophil surfaces by
flow cytometry.[31]

Idiopathic aplastic anaemia

History Exam 1st Test Other tests

prior non-A, B, or C pallor, oedema, »peripheral blood »genetic testing:

hepatitis, exposure to purpura, petechiae, film: normocytic or may identify genetic
drugs; rapid onset of stomatitis mildly macrocytic abnormality
fatigue, fever, rigors, red blood cells, no Complete evaluation
spontaneous bruising, immature precursors for all genetic causes of
mucosal bleeding present
inherited bone marrow
»serum reticulocyte
failure syndromes is
count: low or absent
recommended. Bone
»bone marrow
marrow failure gene
aspirate: hypocellular,
mild dyserythropoiesis panels are becoming
common widely available.
DIAGNOSIS

»bone marrow
trephine biopsy:
hypocellular without
fibrosis or infiltrate
»diepox ybutane
(DEB) test
(peripheral blood
lymphocytes): normal
DEB test for
chromosomal breakage
should be performed
on all patients under
the age of 50 years
to exclude Fanconi's
anaemia, and on
all patients who are
being considered for

36 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Uncommon

Idiopathic aplastic anaemia

History Exam 1st Test Other tests

haematopoietic stem
cell transplantation.[32]

»screening for
parox ysmal
nocturnal
haemoglobinuria
(PNH) clone: may be
detectable in up to 30%
of patients
Presence of a PNH
clone is established
by demonstration
of glycosyl
phosphatidylinositol
(GPI)-linked protein
deficiencies on
red blood cell and
neutrophil surfaces by
flow cytometry.[31]

»peripheral blood,
bone marrow
immunophenotyping:
normal
»peripheral blood,

DIAGNOSIS
bone marrow
cytogenetics:
abnormal clones
present in a minority of
patients

◊ Fanconi's anaemia

History Exam 1st Test Other tests

thrombocytopenia, short stature, structural »peripheral blood »genetic testing: will

leukopenia preceding abnormalities of upper film: red blood cells identify the mutation in
pancytopenia, prior and lower limbs, usually macrocytic most cases
cardiac or genitourinary eyes, ears, gonads; »reticulocyte count:
abnormalities, fatigue, hyperpigmentation, low or absent
spontaneous bruising café au lait spots,
and mucosal bleeding, purpura, petechiae »bone marrow
fever, rigors; may aspirate: hypocellular
have long history of dyserythropoiesis
abnormal findings »diepox ybutane
test (peripheral

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
37
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Uncommon

◊ Fanconi's anaemia

History Exam 1st Test Other tests

blood lymphocytes):
increased chromosomal
breakage

◊ Other rare inherited cytopenias (e.g., Diamond-Blackfan

anaemia, Shwachman-Diamond syndrome, amegakaryocytic
thrombocytopenia)

History Exam 1st Test Other tests

anaemia and/or short stature, »peripheral blood »genetic testing:

thrombocytopenia, characteristic structural film: red blood cells may identify genetic
leukopenia preceding abnormalities of upper usually macrocytic abnormality
pancytopenia, prior and lower limbs, Panels that encompass
»reticulocyte count:
congenital anomalies eyes, and ears; pallor, low or absent all known syndromes
characteristic of any purpura, petechiae
of these syndromes »bone marrow are being developed
(e.g., cardiac, aspirate: hypocellular and improved to
skeletal, genitourinary, dyserythropoiesis evaluate for mutations
orofacial); fatigue, »fetal haemoglobin and deletions.
spontaneous bruising and erythrocyte
and mucosal bleeding, adenosine
fever, rigors; may deaminase activity
have a long history of (Diamond-Blackfan
abnormal findings in anaemia): elevated
particular single cell
cytopenias »pancreatic
enzymes: abnormal
DIAGNOSIS

(in particular stool

elastase; Shwachman-
Diamond syndrome)

◊ Idiopathic portal hypertension

History Exam 1st Test Other tests

gastrointestinal bleeding pallor, ascites, »peripheral blood »bone marrow

secondary to splenomegaly, film: no specific aspirate: hypercellular,
oesophageal varices, hepatomegaly, oedema features erythroid hyperplasia
no history of liver »reticulocyte count: »bone marrow
disease elevated or normal trephine biopsy:
hypercellular, erythroid
»serum liver
hyperplasia
function tests:
normal or mildly
elevated

38 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Uncommon

Chronic myeloid leukaemia

History Exam 1st Test Other tests

fever, chills, malaise, splenomegaly »peripheral blood

weight loss, anorexia film: myeloid maturing
cells, elevated
basophils, eosinophils
»cytogenetics:
Philadelphia
chromosome positive
»bone marrow
biopsy: granulocytic
hyperplasia

◊ Brucellosis

History Exam 1st Test Other tests

travel to high risk splenomegaly, »peripheral blood

areas (e.g., the hepatomegaly, pallor, film: no specific
Mediterranean Basin purpura, petechiae features
[Portugal, Spain, »bone marrow
Southern France, Italy, aspirate: trilineage
Greece, Turkey, North hypercellularity,
Africa], Mexico, South haemophagocytosis
and Central America,
Eastern Europe, Asia, »blood and bone
Africa, the Caribbean, marrow cultures:
the Middle East);[33] positive for organism
fever; myalgia

DIAGNOSIS
◊ Leishmaniasis

History Exam 1st Test Other tests

fever, lymphadenopathy, »peripheral blood

lymphadenopathy, skin splenomegaly, film: rouleaux;
discoloration hepatomegaly, pallor, organisms rarely seen
purpura, petechiae in peripheral blood film
»bone marrow
aspirate: trilineage
hypercellularity;
organisms may be seen
within macrophages
(Leishman-Donovan
bodies)
»bone marrow
trephine
biopsy: trilineage
hypercellularity,

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
39
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Uncommon

◊ Leishmaniasis

History Exam 1st Test Other tests

haemophagocytosis,
small granulomata
»immunochromatographic
or polymerase chain
reaction-based tests
on peripheral blood
or bone marrow
aspirate: positive for
organism

◊ Haemophagocytosis syndromes

History Exam 1st Test Other tests

may be primary (e.g., fever, »peripheral blood »autoimmune

haemophagocytic lymphadenopathy, film: no specific screen: positive
lymphohistiocytosis) hepatosplenomegaly, features antinuclear antibodies
or secondary to a neurological findings (ANA) and anti-ds DNA
»bone marrow
systemic disorder (e.g., in familial disorder aspirate: trilineage Positive ANA and anti-
T-cell lymphoma), (e.g., irritability, ds DNA in systemic
hypercellularity,
malaise, fatigue, neck stiffness, haemophagocytosis lupus erythematosus-
erythematous skin hypotonia, hypertonia,
rash, abdominal convulsions, cranial »blood and bone related cases.[34]
discomfort nerve palsies, marrow cultures:
ataxia, haemiplegia, positive for organism »serum ferritin:
quadriplegia, blindness, 22,470 picomol/L
coma) (>10,000 microgram/L
or 10,000 ng/mL)
DIAGNOSIS

A ferritin level over

22,470 picomol/L
(10,000 microgram/
L or 10,000 ng/mL)
is 90% sensitive
and 96% specific for
haemophagocytic
lymphohistiocytosis in
children.[35]

»molecular genetic
testing: specific
karyotype present
5 disease subtypes
(FHL1 to FHL5) are
described; four genes
have been identified
and characterised:

40 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Uncommon

◊ Haemophagocytosis syndromes

History Exam 1st Test Other tests

FHL1 (unknown gene),
PRF1 (FHL2), UNC13D
(FHL3), and STX11
(FHL4).[36]

◊ Drug-induced immune pancytopenia

History Exam 1st Test Other tests

drug ingestion (e.g., pallor, purpura, »platelet-specific

phenacetin, para- petechiae, rarely mild antibodies: positive
amino salicylic splenomegaly, mild »peripheral blood
acid, rifampicin, jaundice film: no specific
sulfonamides), rapid features
onset of fatigue, easy
bruising, spontaneous »reticulocyte count:
bleeding elevated
»bone marrow
aspirate: hypercellular
»bone marrow
trephine biopsy:
hypercellular

◊ Evans syndrome with associated neutropenia

History Exam 1st Test Other tests

DIAGNOSIS
fatigue, dark urine, pallor, purpura, »peripheral blood »further tests
jaundice, easy bruising, petechiae; film: polychromasia, for autoimmune
spontaneous mucosal lymphadenopathy and spherocytes lymphoproliferative
bleeding hepatosplenomegaly, syndrome (ALPS):
»reticulocyte count:
which may be subtle may be increased
elevated
with a duration >6 double-negative T cells;
months »direct antiglobulin defective lymphocyte
test: positive apoptosis; known
»platelet, ALPS-related germ-line
neutrophil-specific pathological mutation
antibodies: positive or positive results from
other functional assays
»bone marrow
A significant number
aspirate: normal
or trilineage of people with Evans
hypercellularity syndrome have
»bone marrow underlying ALPS.[16]
trephine biopsy: [37] [38]
normal or trilineage
hypercellularity

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
41
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Uncommon

◊ Autoimmune lymphoproliferative syndrome (ALPS)

History Exam 1st Test Other tests

bicytopenia or splenomegaly and/or »T-cell analysis:

pancytopenia, other lymphadenopathy for increased double-
organs (e.g., the liver) >6 months, which may negative T cells
may cause symptoms, be subtle »lymphocyte
may be a family apoptosis: may be
history; in children defective
with autoimmune
bicytopenia or »genetic analysis:
pancytopenia (Evans ALPS-related germ-
syndrome), a diagnostic line mutation may be
work-up for ALPS is detected
strongly suggested[16]
[37]

◊ Systemic lupus erythematosus

History Exam 1st Test Other tests

established connective synovitis, joint »peripheral blood

tissue disorder, joint deformity, malar rash, film: rouleaux
pain, swelling, fatigue, splenomegaly »autoimmune
easy bruising screen: positive
antinuclear antibodies
and anti-double
stranded DNA
»ultrasound of
the abdomen:
DIAGNOSIS

splenomegaly
»bone marrow
aspirate: hypocellular,
dysplastic changes,
haemophagocytosis
»bone marrow
trephine biopsy:
hypocellular, benign
lymphoid aggregates,
bone marrow
fibrosis[39]

◊ Rheumatoid arthritis

History Exam 1st Test Other tests

established connective synovitis, joint deformity »peripheral blood

tissue disorder, joint film: rouleaux

42 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Diagnosis

Uncommon

◊ Rheumatoid arthritis

History Exam 1st Test Other tests

pain, swelling, fatigue, »autoimmune
easy bruising screen: positive
rheumatoid factor
»bone marrow
aspirate: hypocellular,
dysplastic changes,
haemophagocytosis
»bone marrow
trephine biopsy:
hypocellular, benign
lymphoid aggregates
»ultrasound of
the abdomen:
splenomegaly

◊ Infectious mononucleosis

History Exam 1st Test Other tests

malaise, headache, tonsillitis, »serum monospot:

low-grade fever pharyngitis, cervical positive
lymphadenopathy, »peripheral blood
nodal tenderness film: atypical
lymphocytes
»Epstein-Barr
nuclear antibody:

DIAGNOSIS
present
»blood serology
(specific IgM and
IgG titres) for viral
capsid antigen:
positive

◊ Felty syndrome

History Exam 1st Test Other tests

rheumatoid arthritis, splenomegaly »bone marrow

typically precedes other biopsy: myeloid
findings, may be long- hyperplasia with excess
standing (>10 years' of immature forms
duration) »autoimmune
screen: positive
rheumatoid factor

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
43
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Diagnosis

Uncommon

◊ Felty syndrome

History Exam 1st Test Other tests

»ultrasound of
the abdomen:
splenomegaly
DIAGNOSIS

44 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Guidelines

Guidelines

United Kingdom

Diagnosis and management of aplastic anaemia (ht tps://b-s-h.org.uk/

guidelines/guidelines)

Published by: British Society for Haematology

Last published: 2017

International

The 2016 revision to the World Health Organization classification of

myeloid neoplasms and acute leukemia (ht tps://ashpublications.org/blood/
article/127/20/2391/35255/The-2016-revision-to-the-World-Health-Organization)

GUIDELINES
Published by: World Health Organization
Last published: 2016

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
45
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia References

Key articles
• Young NS. Aplastic Anemia. N Engl J Med. 2018 Oct 25;379(17):1643-56. Full text (https://
REFERENCES

www.ncbi.nlm.nih.gov/pmc/articles/PMC6467577) Abstract

• Williams DA, Bennett C, Bertuch A, et al. Diagnosis and treatment of pediatric acquired aplastic
anemia (AAA): an initial survey of the North American Pediatric Aplastic Anemia Consortium
(NAPAAC). Pediatr Blood Cancer. 2014 May;61(5):869-74. Full text (https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC4280184) Abstract

• Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization
classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405. Full
text (http://www.bloodjournal.org/content/127/20/2391.long?sso-checked=true) Abstract

References
1. Saha KC. Diagnosis of arsenicosis. J Environ Sci Health A Tox Hazard Subst Environ
Eng. 2003 Jan;38(1):255-72. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/12635831?
tool=bestpractice.bmj.com)

2. Parker C, Omine M, Richards S, et al; International PNH Interest Group. Diagnosis and management
of paroxysmal nocturnal hemoglobinuria. Blood. 2005 Dec 1;106(12):3699-709. Full text (http://
bloodjournal.hematologylibrary.org/content/106/12/3699.full) Abstract (http://www.ncbi.nlm.nih.gov/
pubmed/16051736?tool=bestpractice.bmj.com)

3. Gregory JJ Jr, Wagner JE, Verlander PC, et al. Somatic mosaicism in Fanconi anemia: evidence
of genotypic reversion in lymphohematopoietic stem cells. Proc Natl Acad Sci U S A. 2001 Feb
27;98(5):2532-7. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/11226273?tool=bestpractice.bmj.com)

4. Chessells JM. Pitfalls in the diagnosis of childhood leukaemia. Br J Haematol. 2001

Sep;114(3):506-11. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/11552974?
tool=bestpractice.bmj.com)

5. Faivre L, Guardiola P, Lewis C, et al. Association of complementation group and mutation

type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group.
Blood. 2000 Dec 15;96(13):4064-70. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/11110674?
tool=bestpractice.bmj.com)

6. Khincha PP, Savage SA. Neonatal manifestations of inherited bone marrow failure syndromes. Semin
Fetal Neonatal Med. 2016 Feb;21(1):57-65. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC4747853) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/26724991?tool=bestpractice.bmj.com)

7. Calado RT, Young NS. Telomere diseases. N Engl J Med. 2009 Dec 10;361(24):2353-65. Abstract
(http://www.ncbi.nlm.nih.gov/pubmed/20007561?tool=bestpractice.bmj.com)

46 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia References
8. Mason PJ, Bessler M. The genetics of dyskeratosis congenita. Cancer Genet. 2011
Dec;204(12):635-45. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/22285015?
tool=bestpractice.bmj.com)

REFERENCES
9. Keller RB, Gagne KE, Usmani GN, et al. Ctc1 mutations in a patient with dyskeratosis
congenita. Pediatr Blood Cancer. 2012 Aug;59(2):311-4. Abstract (http://www.ncbi.nlm.nih.gov/
pubmed/22532422?tool=bestpractice.bmj.com)

10. Perdigones N, Perin JC, Schiano I, et al. Clonal hematopoiesis in patients with dyskeratosis congenita.
Am J Hematol. 2016 Dec;91(12):1227-33. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC5118079) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/27622320?tool=bestpractice.bmj.com)

11. Kirwan M, Dokal I. Dyskeratosis congenita: a genetic disorder of many faces. Clin Genet.
2008 Feb;73(2):103-12. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/18005359?
tool=bestpractice.bmj.com)

12. Appelbaum FR, Barrall J, Storb R, et al. Clonal cytogenetic abnormalities in patients with otherwise
typical aplastic anemia. Exp Hematol. 1987 Dec;15(11):1134-9. Abstract (http://www.ncbi.nlm.nih.gov/
pubmed/3315724?tool=bestpractice.bmj.com)

13. Vulliamy TJ, Marrone A, Knight SW, et al. Mutations in dyskeratosis congenita: their impact on
telomere length and the diversity of clinical presentation. Blood. 2006 Apr 1;107(7):2680-5. Abstract
(http://www.ncbi.nlm.nih.gov/pubmed/16332973?tool=bestpractice.bmj.com)

14. Bluteau O, Sebert M, Leblanc T, et al. A landscape of germ line mutations in a cohort of inherited bone
marrow failure patients. Blood. 2018 Feb 15;131(7):717-32. Full text (http://www.bloodjournal.org/
content/131/7/717.long?sso-checked=true) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/29146883?
tool=bestpractice.bmj.com)

15. Cines DB, Liebman H, Stasi R. Pathobiology of secondary immune thrombocytopenia. Semin
Hematol. 2009 Jan;46(1 Suppl 2):S2-14. Full text (http://www.ncbi.nlm.nih.gov/pmc/articles/
PMC2682438/?tool=pubmed) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/19245930?
tool=bestpractice.bmj.com)

16. Norton A, Roberts I. Management of Evans syndrome. Br J Haematol. 2006 Jan;132(2):125-37.

Full text (http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2005.05809.x/full) Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/16398647?tool=bestpractice.bmj.com)

17. Camitta BM, Rappeport JM, Parkman R, et al. Selection of patients for bone marrow transplantation
in severe aplastic anemia. Blood. 1975 Mar;45(3):355-63. Full text (http://www.bloodjournal.org/
content/bloodjournal/45/3/355.full.pdf) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/1090310?
tool=bestpractice.bmj.com)

18. Bacigalupo A, Hows J, Gluckman E, et al. Bone marrow transplantation (BMT) versus
immunosuppression for the treatment of severe aplastic anaemia (SAA): a report of the EBMT
SAA working party. Br J Haematol. 1988 Oct;70(2):177-82. Abstract (http://www.ncbi.nlm.nih.gov/
pubmed/3056497?tool=bestpractice.bmj.com)

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
47
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia References
19. Killick SB, Bown N, Cavenagh J, et al; British Society for Standards in Haematology. Guidelines for the
diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016 Jan;172(2):187-207. Full
text (http://onlinelibrary.wiley.com/doi/10.1111/bjh.13853/full) Abstract (http://www.ncbi.nlm.nih.gov/
REFERENCES

pubmed/26568159?tool=bestpractice.bmj.com)

20. Young NS. Aplastic Anemia. N Engl J Med. 2018 Oct 25;379(17):1643-56. Full text (https://
www.ncbi.nlm.nih.gov/pmc/articles/PMC6467577) Abstract (http://www.ncbi.nlm.nih.gov/
pubmed/30354958?tool=bestpractice.bmj.com)

21. Weinzierl EP, Arber DA. The differential diagnosis and bone marrow evaluation of new-onset
pancytopenia. Am J Clin Pathol. 2013 Jan;139(1):9-29. Full text (https://academic.oup.com/
ajcp/article/139/1/9/1765887) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/23270895?
tool=bestpractice.bmj.com)

22. Williams DA, Bennett C, Bertuch A, et al. Diagnosis and treatment of pediatric acquired aplastic
anemia (AAA): an initial survey of the North American Pediatric Aplastic Anemia Consortium
(NAPAAC). Pediatr Blood Cancer. 2014 May;61(5):869-74. Full text (https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC4280184) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/24285674?
tool=bestpractice.bmj.com)

23. Desai AV, Perpich M, Godley LA. Clinical assessment and diagnosis of germline predisposition
to hematopoietic malignancies: the University of Chicago experience. Front Pediatr. 2017 Dec
6;5:252. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723667) Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/29270394?tool=bestpractice.bmj.com)

24. Weinzierl EP, Arber DA. Bone marrow evaluation in new-onset pancytopenia. Hum Pathol.
2013 Jun;44(6):1154-64. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/23332933?
tool=bestpractice.bmj.com)

25. Jain A, Naniwadekar M. An etiological reappraisal of pancytopenia - largest series reported to date
from a single tertiary care teaching hospital. BMC Hematol. 2013 Nov 6;13(1):10. Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/24238033?tool=bestpractice.bmj.com)

26. Savage RA, Hoffman GC, Shaker K. Diagnostic problems involved in detection of metastatic
neoplasms by bone marrow aspirate compared with needle biopsy. Am J. Clin Pathol. 1978
Oct;70(4):623-7. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/707429?tool=bestpractice.bmj.com)

27. Sanz MA, Martin G, Gonzalez M, et al. Risk-adapted treatment of acute promyelocytic leukemia with
all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA
group. Blood. 2004 Feb 15;103(4):1237-43. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/14576047?
tool=bestpractice.bmj.com)

28. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization
classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405.
Full text (http://www.bloodjournal.org/content/127/20/2391.long?sso-checked=true) Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/27069254?tool=bestpractice.bmj.com)

48 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia References
29. Janckila AJ, Wallace JH, Yam LT. Generalized monocyte deficiency in leukaemic reticuloendotheliosis.
Scand J Haematol. 1982 Aug;29(2):153-60. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/6753123?
tool=bestpractice.bmj.com)

REFERENCES
30. Bernasconi P, Boni M, Cavigliano PM, et al. Clinical relevance of cytogenetics in myelodysplastic
syndromes. Ann N Y Acad Sci. 2006 Nov;1089:395-410. Abstract (http://www.ncbi.nlm.nih.gov/
pubmed/17261783?tool=bestpractice.bmj.com)

31. Dezern AE, Borowitz MJ. ICCS/ESCCA consensus guidelines to detect GPI-deficient cells in
paroxysmal nocturnal hemoglobinuria (PNH) and related disorders part 1 - clinical utility. Cytometry
B Clin Cytom. 2018 Jan;94(1):16-22. Full text (https://onlinelibrary.wiley.com/doi/full/10.1002/
cyto.b.21608) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/29236352?tool=bestpractice.bmj.com)

32. International Agranulocytosis and Aplastic Anemia Study Group. Incidence of aplastic anemia: the
relevance of diagnostic criteria. Blood. 1987 Dec;70(6):1718-21. Abstract (http://www.ncbi.nlm.nih.gov/
pubmed/3676511?tool=bestpractice.bmj.com)

33. Centers for Disease Control and Prevention. Brucellosis: areas at risk. November 2012 [internet
publication]. Full text (https://www.cdc.gov/brucellosis/exposure/areas.html)

34. Pereira RM, Velloso ER, Menezes, et al. Bone marrow findings in systemic lupus erythematosus
patients with peripheral cytopenias. Clin Rheum. 1998;17(3):219-22. Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/9694056?tool=bestpractice.bmj.com)

35. CE Allen, Yu X, Kozinetz CA, et al. Highly elevated ferritin levels and the diagnosis of
hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008 Jun;50(6):1227-35. Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/18085676?tool=bestpractice.bmj.com)

36. Sieni E, Cetica V, Hackmann Y, et al. Familial hemophagocytic lymphohistiocytosis: when rare
diseases shed light on immune system functioning. Front Immunol. 2014 Apr 16;5:167. Full text
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997030) Abstract (http://www.ncbi.nlm.nih.gov/
pubmed/24795715?tool=bestpractice.bmj.com)

37. Seif AE, Manno CS, Sheen C, et al. Identifying autoimmune lymphoproliferative syndrome in
children with Evans syndrome: a multi-institutional study. Blood. 2010 Mar 18;115(11):2142-5. Full
text (http://www.bloodjournal.org/content/115/11/2142.long?sso-checked=true) Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/20068224?tool=bestpractice.bmj.com)

38. Oliveira JB, Bleesing JJ, Dianzani U, et al. Revised diagnostic criteria and classification for the
autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop.
Blood. 2010 Oct 7;116(14):e35-40. Full text (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953894)
Abstract (http://www.ncbi.nlm.nih.gov/pubmed/20538792?tool=bestpractice.bmj.com)

39. Chalayer E, Costedoat-Chalumeau N, Beyne-Rauzy O, et al. Bone marrow involvement in systemic

lupus erythematosus. QJM. 2017 Nov 1;110(11):701-11. Abstract (http://www.ncbi.nlm.nih.gov/
pubmed/28525589?tool=bestpractice.bmj.com)

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
49
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Images

Images
IMAGES

Figure 1: Table of aetiologies for pancytopenia (SLE: systemic lupus erythematosus, CMV: cytomegalovirus,
EBV: Epstein-Barr virus, GVHD: graft-versus-host disease)
From the collection of Jeff K. Davies

50 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Images

IMAGES
Figure 2: Hypoplastic myelodysplastic syndrome with dysplastic normoblasts
Morris Edelman, MD and Peihong Hsu, MD

Figure 3: Aplastic anaemia: normocellular bone marrow is shown on the left; and empty marrow, typical of
congenital or acquired aplastic anaemia, is shown on the right
Morris Edelman, MD and Peihong Hsu, MD

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
51
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
IMAGES Assessment of pancytopenia Images

Figure 4: Flow diagram for evaluation of pancytopenia. Abbreviations: PNH, paroxysmal nocturnal
haemoglobinuria; IBMFS, inherited bone marrow failure syndromes
From the collection of Jeff K. Davies

52 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Images

IMAGES
Figure 5: Icterus or jaundice
CDC. Dr Thomas F. Sellers/Emory University; used with permission

Figure 6: Angular cheilitis

From the collection of Dr Wanda C. Gonsalves; patient consent obtained

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
53
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
IMAGES Assessment of pancytopenia Images

Figure 7: Gingival enlargement, petechiae and bleeding in acute myeloid leukaemia

Collection of Giuseppina Campisi, DDS, MS and Giuseppe Pizzo, DDS

54 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Images
Figure 8: Clubbing of nails showing loss of the classic Lovibond's angle
From the collection of Dr Murlidhar Rajagopalan

IMAGES
Figure 9: Café au lait spots on the back of a young boy
From the personal collection of Dr Vincent M. Riccardi; used with permission

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
55
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
 Assessment of pancytopenia Disclaimer

Disclaimer
BMJ Best Practice is intended for licensed medical professionals. BMJ Publishing Group Ltd (BMJ) does not
advocate or endorse the use of any drug or therapy contained within this publication nor does it diagnose
patients. As a medical professional you retain full responsibility for the care and treatment of your patients
and you should use your own clinical judgement and expertise when using this product.

This content is not intended to cover all possible diagnosis methods, treatments, follow up, drugs and any
contraindications or side effects. In addition, since such standards and practices in medicine change as
new data become available, you should consult a variety of sources. We strongly recommend that you
independently verify specified diagnosis, treatments and follow-up and ensure it is appropriate for your
patient within your region. In addition, with respect to prescription medication, you are advised to check the
product information sheet accompanying each drug to verify conditions of use and identify any changes in
dosage schedule or contraindications, particularly if the drug to be administered is new, infrequently used, or
has a narrow therapeutic range. You must always check that drugs referenced are licensed for the specified
use and at the specified doses in your region.

Information included in BMJ Best Practice is provided on an “as is” basis without any representations,
conditions or warranties that it is accurate and up to date. BMJ and its licensors and licensees assume no
responsibility for any aspect of treatment administered to any patients with the aid of this information. To
the fullest extent permitted by law, BMJ and its licensors and licensees shall not incur any liability, including
without limitation, liability for damages, arising from the content. All conditions, warranties and other terms
which might otherwise be implied by the law including, without limitation, the warranties of satisfactory
quality, fitness for a particular purpose, use of reasonable care and skill and non-infringement of proprietary
rights are excluded.

Where BMJ Best Practice has been translated into a language other than English, BMJ does not warrant the
accuracy and reliability of the translations or the content provided by third parties (including but not limited to
local regulations, clinical guidelines, terminology, drug names and drug dosages). BMJ is not responsible for
any errors and omissions arising from translation and adaptation or otherwise.Where BMJ Best Practice lists
drug names, it does so by recommended International Nonproprietary Names (rINNs) only. It is possible that
certain drug formularies might refer to the same drugs using different names.

Please note that recommended formulations and doses may differ between drug databases drug names and
brands, drug formularies, or locations. A local drug formulary should always be consulted for full prescribing
information.
DISCLAIMER

Treatment recommendations in BMJ Best Practice are specific to patient groups. Care is advised when
selecting the integrated drug formulary as some treatment recommendations are for adults only, and external
links to a paediatric formulary do not necessarily advocate use in children (and vice-versa). Always check
that you have selected the correct drug formulary for your patient.

Where your version of BMJ Best Practice does not integrate with a local drug formulary, you should consult
a local pharmaceutical database for comprehensive drug information including contraindications, drug
interactions, and alternative dosing before prescribing.

Interpretation of numbers

Regardless of the language in which the content is displayed, numerals are displayed according to the
original English-language numerical separator standard. For example 4 digit numbers shall not include a
comma nor a decimal point; numbers of 5 or more digits shall include commas; and numbers stated to be
less than 1 shall be depicted using decimal points. See Figure 1 below for an explanatory table.

BMJ accepts no responsibility for misinterpretation of numbers which comply with this stated numerical
separator standard.

This approach is in line with the guidance of the International Bureau of Weights and Measures Service.

Figure 1 – BMJ Best Practice Numeral Style

56 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Assessment of pancytopenia Disclaimer
5-digit numerals: 10,000

4-digit numerals: 1000

numerals < 1: 0.25

Our full website and application terms and conditions can be found here: Website Terms and Conditions.

Contact us

+ 44 (0) 207 111 1105

support@bmj.com

BMJ
BMA House
Tavistock Square
London
WC1H 9JR
UK

DISCLAIMER

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Sep 10, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
57
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2021. All rights reserved.
Contributors:

// Authors:

Jeffrey M. Lipton, MD, PhD

Frances and Thomas Gambino Professor of Pediatrics in Hematology/Oncology
Professor of Pediatrics and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/
Northwell, Professor, The Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein
Institute for Medical Research, Director, Hematology/Oncology and Stem Cell Transplantation, Cohen
Children's Medical Center of New York, Hyde Park, New York
DISCLOSURES: JML declares that he has no competing interests.

// Acknowledgements:
Dr Jeffrey M. Lipton would like to gratefully acknowledge Dr Jeff K. Davies and Dr Eva C. Guinan, the
previous contributors to this topic.
DISCLOSURES: JKD and ECG declare that they have no competing interests.

// Peer Reviewers:

Stella Davies, MD, PhD

Professor and Division Director
Cincinnati Children's Hospital Medical Center, Cincinnati, OH
DISCLOSURES: SD declares that she has no competing interests.

Drew Provan, BSc, MBChB

Consultant Hematologist
Department of Hematology, The Royal London Hospital, London, UK
DISCLOSURES: DP was medical director at GlaxoSmithKline 2005-2006.

Alfred P. Gillio, MD
Director
Bone Marrow Failure Clinic, Tomorrows Children's Institute, Hackensack University Medical Center,
Hackensack, NJ
DISCLOSURES: APG declares that he has no competing interests.