Académique Documents
Professionnel Documents
Culture Documents
Overview 4
Aetiology 4
Emergencies 8
Urgent considerations 8
Red flags 8
Diagnosis 9
References 35
Images 37
Disclaimer 39
Summary
Pancytopenia is a reduction in the number of RBCs, WBCs, and platelets in the peripheral blood below the lower
limits of the age-adjusted normal range for healthy people. It is therefore the combination of anaemia, leukopenia,
and thrombocytopenia. It may result from decreased production of blood cells or bone marrow failure, or from
their immune-mediated destruction or non-immune-mediated sequestration in the periphery. The diagnosis is
made from the results of an automated FBC.
Assessment of pancytopenia Overview
Aetiology
Pancytopenia may be due to decreased bone marrow production or bone marrow failure, clonal disorders of
haematopoiesis, increased non-immune-mediated destruction or sequestration, or an immune-mediated destruction
OVERVIEW
of blood cells.
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Assessment of pancytopenia Overview
OVERVIEW
requires adequate nutritional status, particularly vitamin B12 and folic acid, and trace amounts of other elements.
Chemotherapy is a common cause of transient pancytopenia, although this rarely presents a diagnostic dilemma,
most commonly resolving within 1 to 2 weeks. Some regimens are associated with significantly longer periods of
pancytopenia. The most common cause of transient pancytopenia in all age groups is cytotoxic chemotherapy
and radiotherapy.
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 GI 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.
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 (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.
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
(see further below), as has parvovirus in individuals with specific predisposing conditions (most prominently sickle
cell anaemia).
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 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).
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Assessment of pancytopenia Overview
Fanconi's anaemia is primarily an autosomal recessive disorder where a variety of dysfunctional proteins result in
decreased haematopoiesis and BMF.[3] In addition, 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]
OVERVIEW
Dyskeratosis congenita (DC) arises from genetic lesions that compromise telomere integrity, with resulting loss of
cell self-renewal and regeneration.[6] Mutations in genes associated with telomere biology can be identified in
approximately 50% of patients with clinical features of classic DC.[7] [8] Classic DC is defined by nail dystrophy,
mucosal leukoplakia, and skin pigmentation changes, all ranging in severity from virtually non-existent to severe.
Other abnormalities include BMF, premature balding and grey hair, urethral strictures, excessive tear production,
and pulmonary fibrosis.[9]
IAA is a rare acquired condition (2-6 cases per million general population). The diagnosis of IAA requires the presence
of pancytopenia in combination with decreased bone marrow cellularity without infiltration or fibrosis.[10] IAA is
therefore a diagnosis of exclusion and has to be differentiated carefully from congenital and inherited BMF
syndromes.[11] 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 condition.
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.
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.[12]
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),[13]
although other targets are less commonly involved (e.g., autoimmune hepatitis).
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Assessment of pancytopenia Overview
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:
OVERVIEW
Connective tissue disorders (most commonly rheumatoid arthritis and systemic lupus erythematosus)
Mycobacterial infection
Infectious mononucleosis
HIV has also been associated with pancytopenia secondary to underproduction of blood cells
Felty's syndrome (rheumatoid arthritis, splenomegaly, and neutropenia) may also be associated with pancytopenia.
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Assessment of pancytopenia Emergencies
Urgent considerations
(See Differential diagnosis for more details)
symptoms usually reflect BMF. 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 CNS involvement is present. Treatment uses multi-agent dose-intense chemotherapy regimens in induction,
consolidation, and maintenance phases. In all cases of severe pancytopenia (symptomatic anaemia, WBC <0.5 x 10^9/L
[<500/microlitre], and platelets <20 x 10^9/L [<20 x 10^3/microlitre]), investigation is mandatory within 24 to 48 hours.
Supportive therapy with RBC 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.
neutrophils <0.5 x 10^9/L (<500/microlitre) (very severe aplastic anaemia <0.2 x 10^9/L [<200/microlitre])
Clinical history plus most signs and symptoms usually reflect BMF. These include fatigue, dyspnoea, dizziness, bleeding,
easy bruising, and recurrent infections. In all cases of severe pancytopenia (symptomatic anaemia and findings as above),
investigation is mandatory within 24 to 48 hours. Supportive therapy with RBC 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.
Red flags
Acute myeloid leukaemia
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Assessment of pancytopenia 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
A thorough history and physical examination are always required, preferably conducted by a haematologist. An FBC and
DIAGNOSIS
examination of peripheral blood film by a haematologist are essential. Bone marrow examination by aspirate and biopsy
is almost always required as well.
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, aplastic anaemia,
inherited bone marrow failure syndromes (IBMFS), early fetal loss, history of cancer, metabolic disorders, liver disease, or
connective tissue disorders.
The most common cause of transient pancytopenia in all age groups is cytotoxic chemotherapy and radiotherapy. The
symptoms and signs of pancytopenia relate to the blood cell lineages affected (RBCs, WBCs, and platelets). Mild
pancytopenia is often symptomless and detected incidentally when an FBC is performed for another reason, particularly
in association with non-specific viral illnesses in children. Spontaneous mucosal bleeding (gums, GI 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).
In children with autoimmune bicytopenia or pancytopenia (Evans' syndrome), a diagnostic work-up for autoimmune
lymphoproliferative syndrome (ALPS) is strongly suggested.[13] [14] Although lymphadenopathy and splenomegaly are
common, they may be subtle. The currently accepted definitive diagnostic criteria are splenomegaly and/or
lymphadenopathy for >6 months and increased double-negative T cells, as well as either defective lymphocyte apoptosis
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Assessment of pancytopenia Diagnosis
or a known ALPS-related germ-line pathological mutation. In addition to the required criteria, a probable diagnosis requires
autoimmune cytopenias, a family history of benign lymphoproliferation, consistent immunohistochemistry, or any
elevation in plasma sFASL (soluble FAS ligand), interleukin-10, or vitamin B12.[15]
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) and malignancy. Spontaneous mucosal
bleeding (gums, GI 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 systemic lupus erythematosus (SLE), and sore throat mononucleosis.
The following reference points to specific organ systems and associated conditions and is helpful to guide the examination.
Eye examination
Oral examination
Cardiovascular examination
DIAGNOSIS
Evidence of prior cardiac surgery (cardiac disease associated with congenital syndromes)
Respiratory examination
Abdominal examination
Skin examination
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Assessment of pancytopenia Diagnosis
Purpura/bruising (thrombocytopenia)
Hypopigmented areas
Musculoskeletal examination
Swelling/synovitis (SLE)
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.
Laboratory
An FBC and examination of peripheral blood film by a haematologist are essential. A standard battery of evaluative tests
may include:
DIAGNOSIS
Serum coagulation profile, bleeding time, fibrinogen, and D-dimer
Fanconi's anaemia: diepoxybutane (DEB) test for chromosomal breakage in peripheral blood lymphocytes
Epstein-Barr: serum monospot, viral capsid antigen (VCA), and Epstein-Barr nuclear antibody (EBNA)
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Assessment of pancytopenia Diagnosis
Leishmaniasis and other rare infections: blood and bone marrow culture, serum ELISA
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 (reduced cellularity indicates decreased production of blood
cells, whereas normal/increased cellularity indicates ineffective production or increased destruction or sequestration
of blood cells).
Cytology (megaloblastic change, dysplastic changes, abnormal cell infiltrates, haemophagocytosis, and infection
[e.g., Leishman-Donovan bodies])
Normal or increased in MDS, acute and chronic leukaemia, myeloma with plasma cells, carcinomatous 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.
Cellular infiltration
Blasts
DIAGNOSIS
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.[16] In some other parts of the world, hypersplenism and infection are the most frequent aetiologies
of pancytopenia.[17]
Radiology
Abdominal ultrasound scan or CT scan of the abdomen is indicated to evaluate for splenomegaly. CXR 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.
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Assessment of pancytopenia Diagnosis
Common
Chemotherapy
Radiotherapy
Non-Hodgkin's lymphoma
Myelodysplasia
Cirrhosis
Hepatitis B
Hepatitis C
DIAGNOSIS
Autoimmune hepatitis
HIV
Cytomegalovirus infection
Mycobacterial infection
Uncommon
Multiple myeloma
Myelofibrosis
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Assessment of pancytopenia Diagnosis
Uncommon
Anorexia nervosa
Graft-versus-host disease
Dyskeratosis congenita
Fanconi's anaemia
Brucellosis
Leishmaniasis
DIAGNOSIS
Haemophagocytosis syndromes
Rheumatoid arthritis
Infectious mononucleosis
Felty's syndrome
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Assessment of pancytopenia Diagnosis
Differential diagnosis
Common
Chemotherapy
Radiotherapy
DIAGNOSIS
megaloblastosis
serum reticulocyte
count: usually low
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Assessment of pancytopenia Diagnosis
Common
to gross anisocytosis.
serum reticulocyte
count: usually low
serum RBC folate: low in
folate deficiency
bone marrow aspirate:
hypercellular,
megaloblastic
erythroblasts, giant
metamyelocytes
serum LDH: moderately
raised
serum bilirubin:
moderately raised, mostly
indirect
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Assessment of pancytopenia Diagnosis
Common
breast, prostate, lung, cachexia, finger clubbing, peripheral blood film: CT of abdomen: may
thyroid, kidney, GI breast lump, leuko-erythroblastic cell reveal abdominal or renal
malignancy or metastatic lymphadenopathy, forms mass
melanoma in adults; enlarged irregular prostate, bone marrow aspirate: serum
neuroblastoma, abdominal mass clumps of tumour cells prostatic-specific
rhabdomyosarcoma, Aspirate may be dry antigen: elevated in
Ewing's sarcoma, (non-diagnostic) or normal prostate cancer
retinoblastoma in children; when infiltration is
weight loss, anorexia, thyroid ultrasound:
detectable on the trephine
fatigue irregular mass or nodule
roll or trephine biopsy.[18]
breast imaging: mass or
CXR: mass (lung cancer) calcifications
serum LFTs: elevated
ALT and AST ( hepatic
metastases)
serum coagulation
profile: prolonged PT and
PTT
serum fibrinogen and
D-dimer: diminished
fibrinogen and elevated
D-dimer (indicative of
chronic disseminated
intravascular coagulation)
Common in
mucin-secreting
adenocarcinoma (e.g.,
DIAGNOSIS
prostate).
Non-Hodgkin's lymphoma
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Assessment of pancytopenia Diagnosis
Common
Non-Hodgkin's lymphoma
gradual onset of fatigue, cachexia, peripheral blood film: lymph node biopsy:
weight loss, lymphadenopathy, circulating leukaemia cells lymphoproliferative
lymphadenopathy, fever, hepatosplenomegaly disorder
bone marrow aspirate:
rigors, respiratory distress, increased proportion of
abdominal distention lymphoid cells
immunophenotyping
(of peripheral blood or
bone marrow): clonal
population of lymphoid
cells
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Assessment of pancytopenia Diagnosis
Common
Myelodysplasia
incidental presentation pallor, oedema, purpura, or peripheral blood film: cytogenetics: may be
common, gradual onset of petechiae may have irregular or abnormal
fatigue, shortness of macrocytic RBCs, Cytogenetic abnormalities
breath, recurrent infection, dysplastic granulocytes, can be detected in 40% to
easy bruising, spontaneous platelets may be large and 70% of de novo MDS cases,
mucosal bleeding, hypogranular and 95% of secondary MDS
abdominal fullness cases.[22]
serum reticulocyte
count: usually low, may be
normal or raised
bone marrow aspirate:
usually hypercellular,
rarely, hypocellular
(hypocellular
myelodysplasia [MDS]),
dysplastic changes
Cirrhosis
liver disease secondary to pallor, jaundiced sclerae, peripheral blood film: bone marrow aspirate:
viral, autoimmune, or abdominal distension, macrocytes, target cells, hypercellular, erythroid
alcoholic hepatitis ascites, stomatocytes, hyperplasia
hepatosplenomegaly acanthocytes
reticulocyte count:
elevated or normal
DIAGNOSIS
serum LFTs: elevated
Hepatitis B
IV drug use pallor, jaundice, abdominal peripheral blood film: bone marrow aspirate:
pain, ascites, macrocytes, target cells, hypercellular, erythroid
hepatosplenomegaly stomatocytes, hyperplasia
acanthocytes
reticulocyte count:
elevated or normal
serum LFTs: elevated
serum HBsAg: positive
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Assessment of pancytopenia Diagnosis
Common
Hepatitis C
IV drug use or transfusion, pallor, jaundice, ascites, peripheral blood film: bone marrow aspirate:
fatigue, myalia, arthralgia spider haemangiomata macrocytes, target cells, hypercellular, erythroid
stomatocytes, hyperplasia
acanthocytes
reticulocyte count:
elevated or normal
serum LFTs: elevated
serum antihepatitis C
virus (HCV): presence of
HCV antibodies
Autoimmune hepatitis
fatigue, malaise, anorexia, pallor, jaundice, ascites, peripheral blood film: bone marrow aspirate:
nausea, pruritus hepatosplenomegaly, macrocytes, target cells, hypercellular, erythroid
encephalopathy stomatocytes, hyperplasia
acanthocytes
reticulocyte count:
elevated or normal
serum LFTs: elevated
autoantibody screen:
positive
DIAGNOSIS
HIV
HIV disease or risk factors, cachexia, generalised peripheral blood film: protein electrophoresis:
influenza-like illness (acute lymphadenopathy, atypical lymphocytes polyclonal
seroconversion), fatigue, HIV-associated skin lesions (acute seroconversion), hypergammaglobulinaemia
easy bruising, spontaneous (oral hairy leukoplakia, rouleaux, dysplastic
bleeding, fever, rigors molluscum contagiosum, neutrophils
(chronic HIV disease) Kaposi's sarcoma) reticulocyte count:
reduced
HIV serology: positive
bone marrow aspirate:
hypercellular (acute
seroconversion),
hypocellular,
dyserythropoiesis
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Assessment of pancytopenia Diagnosis
Common
Cytomegalovirus infection
Mycobacterial infection
DIAGNOSIS
haemophagocytosis
bone marrow trephine
biopsy: reduced cellularity,
granulomas, fibrosis
bone marrow culture:
positive for organism
Uncommon
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Assessment of pancytopenia Diagnosis
Uncommon
Diagnosis of acute
leukaemia can be made
with less than 20% blasts
in the bone marrow in
erythroleukaemia or when
a characteristic
chromosomal abnormality
is detected.[20] Rarely, the
bone marrow may be
hypocellular.
Immunophenotyping is
essential to differentiate
hypoplastic acute
leukaemia from aplastic
anaemia.
DIAGNOSIS
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Assessment of pancytopenia Diagnosis
Uncommon
Multiple myeloma
gradual onset of fatigue, pallor, vertebral collapse; peripheral blood film: radiological skeletal
weight loss, fever, rigors, less commonly rouleaux, circulating survey: lytic lesions
back pain, constipation hyperviscosity syndrome plasma cells may rarely be and/or osteopenia
(due to hypercalcaemia), (purpura, visual defects, present
bone pain confusion, neuropathy) bone marrow aspirate:
plasma cell infiltrate,
abnormal plasma cells,
plasmablasts
immunophenotyping
(of peripheral blood or
bone marrow): plasma
cells exhibit restriction of
DIAGNOSIS
kappa or lambda light
chain expression
serum and urine
electrophoresis :
monoclonal serum protein
and urinary Bence Jones
proteins (light chains)
detected
Myelofibrosis
gradual onset of fatigue, cachexia, pallor, peripheral blood film: serum and RBC folate:
weight loss, fever, night splenomegaly, leuko-erythroblastic, tear usually diminished
sweats, LUQ discomfort hepatomegaly drop RBCs serum B12: usually
bone marrow aspirate: elevated
hypercellular and fibrotic,
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Assessment of pancytopenia Diagnosis
Uncommon
Myelofibrosis
Anorexia nervosa
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Assessment of pancytopenia Diagnosis
Uncommon
Graft-versus-host disease
DIAGNOSIS
environmental exposure pallor, jaundice, signs of peripheral blood film:
(wood, glass production, portal hypertension may basophilic stippling
semiconductor industry, be present bone marrow aspirate:
smelting, pesticides), hypocellular without
headaches, abdominal pain infiltrate or fibrosis,
decreased haematopoietic
cells, dyserythropoiesis
bone marrow trephine
biopsy: hypocellular
without infiltration or
fibrosis dyserythropoiesis
DEB test: normal
screening for PNH
clone: negative
arsenic level (serum,
urine, hair, nails):
elevated
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Assessment of pancytopenia Diagnosis
Uncommon
Dyskeratosis congenita
DIAGNOSIS
presents in the third or nail and skin atrophy, peripheral blood film: genetic studies: may
fourth decade of life, blocked tear ducts, red cells usually identify 1 of several
fatigue, spontaneous urethral meatal stenosis, macrocytic genetic mutations
bruising and mucosal reticulated skin Dyskeratosis congenita
reticulocyte count: low
bleeding, fever, rigors (less pigmentation, pallor, (DC) is genetically
or absent
common), chronic tearing, purpura, petechiae heterogeneous and in
difficulty with urination bone marrow aspirate: many cases the genetic
hypocellular, reduced lesion has not been
haematopoietic cells, identified. Aplasia only
dyserythropoiesis occurs in X-linked and
common autosomal recessive forms
bone marrow trephine of DC. In kindreds where
biopsy: hypocellular the genetic lesion is
without infiltration or known, screening of
fibrosis potential related
haematopoietic stem cell
DEB test: normal donors is useful.[11]
(peripheral blood
lymphocytes)
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Assessment of pancytopenia Diagnosis
Uncommon
Dyskeratosis congenita
previous venous pallor, jaundice, portal peripheral blood film: DEB test: normal
thrombosis, fatigue, hypertension polychromasia screening for PNH
intermittent abdominal reticulocyte count: clone: positive
pain and dark urine, blood
DIAGNOSIS
relative reticulocytosis The most sensitive assay
in stool for detecting a PNH clone
bone marrow aspirate:
is flow cytometry of
hypocellular, reduced
granulocyte expression of
haematopoietic cells, mast
PIG-linked molecules, and
cells may be increased
is not affected by red cell
transfusion [23]
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Assessment of pancytopenia Diagnosis
Uncommon
screening for
paroxysmal nocturnal
haemoglobinuria clone
(peripheral blood, bone
marrow): detectable in up
to 30% of patients
DIAGNOSIS
Fanconi's anaemia
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Assessment of pancytopenia Diagnosis
Uncommon
Fanconi's anaemia
GI bleeding secondary to pallor, ascites, peripheral blood film: no bone marrow aspirate:
oesophageal varices, no hx splenomegaly, specific features hypercellular, erythroid
of liver disease hepatomegaly, oedema hyperplasia
reticulocyte count:
elevated or normal bone marrow trephine
biopsy: hypercellular,
serum LFTs: normal or
erythroid hyperplasia
mildly elevated
DIAGNOSIS
weight loss, anorexia myeloid maturing cells,
elevated basophils,
eosinophils
cytogenetics:
Philadelphia chromosome
positive
bone marrow biopsy:
granulocytic hyperplasia
Brucellosis
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Assessment of pancytopenia Diagnosis
Uncommon
Brucellosis
Leishmaniasis
Haemophagocytosis syndromes
may be primary (e.g., fever, lymphadenopathy, peripheral blood film: no autoimmune screen:
haemophagocytic hepatosplenomegaly, specific features positive ANA and anti-ds
lymphohistiocytosis) or neurological findings in DNA
bone marrow aspirate:
secondary to a systemic familial disorder (e.g., Positive ANA and anti-ds
trilineage hypercellularity,
disorder (e.g., T-cell irritability, neck stiffness, DNA in SLE-related
haematophagocytosis
lymphoma), malaise, hypotonia, hypertonia, cases.[25]
fatigue, erythematous skin convulsions, cranial nerve blood and bone marrow
rash, abdominal discomfort palsies, ataxia, haemiplegia, cultures: positive for serum ferritin: 22,470
quadriplegia, blindness, organism picomol/L (>10,000
coma) microgram/L or 10,000
ng/mL)
A ferritin level over 22,470
picomol/L (10,000
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Assessment of pancytopenia Diagnosis
Uncommon
Haemophagocytosis syndromes
microgram/L or 10,000
ng/mL) is 90% sensitive
and 96% specific for
haemophagocytic
lymphohistiocytosis in
children.[26]
molecular genetic
testing: specific karyotype
present
4 disease subtypes (FHL1,
FHL2, FHL3, and FHL4) are
described; 3 genes have
been identified and
characterised: PRF1 (FHL2),
UNC13D (FHL3), and
STX11 (FHL4).[27]
DIAGNOSIS
spontaneous bleeding reticulocyte count:
elevated
bone marrow aspirate:
hypercellular
bone marrow trephine
biopsy: hypercellular
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Assessment of pancytopenia Diagnosis
Uncommon
platelet,
neutrophil-specific
antibodies: positive
bone marrow aspirate:
normal or trilineage
hypercellularity
bone marrow trephine
biopsy: normal or
trilineage hypercellularity
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Assessment of pancytopenia Diagnosis
Uncommon
benign lymphoid
aggregates
Rheumatoid arthritis
Infectious mononucleosis
DIAGNOSIS
History Exam 1st Test Other tests
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Assessment of pancytopenia Diagnosis
Uncommon
Felty's syndrome
Diagnostic guidelines
Europe
Published by: British Committee for Standards in Haematology Last published: 2015
Summary: Guidelines constructed using published literature and expert and consensus opinion. Diagnostic
investigations are detailed. Key recommendations are clearly highlighted throughout the document.
DIAGNOSIS
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Assessment of pancytopenia References
Key articles
REFERENCES
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of
myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937-951. Abstract
References
1. Saha KC. Diagnosis of arsenicosis. J Environ Sci Health A Tox Hazard Subst Environ Eng. 2003;38:255-272. Abstract
2. Parker C, Omine M, Richards S, et al; International PNH Interest Group. Diagnosis and management of paroxysmal
nocturnal hemoglobinuria. Blood. 2005;106:3699-3709. Full text Abstract
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;98:2532-2537. Abstract
4. Chessells JM. Pitfalls in the diagnosis of childhood leukaemia. Br J Haematol. 2001;114:506-511. Abstract
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;96:4064-4070. Abstract
6. Calado RT, Young NS. Telomere diseases. N Engl J Med. 2009;361:2353-2365. Abstract
7. Mason PJ, Bessler M. The genetics of dyskeratosis congenita. Cancer Genet. 2011;204:635-645. Abstract
8. Keller RB, Gagne KE, Usmani GN, et al. Ctc1 mutations in a patient with dyskeratosis congenita. Pediatr Blood Cancer.
2012;59:311-314. Abstract
9. Kirwan M, Dokal I. Dyskeratosis congenita: a genetic disorder of many faces. Clin Genet. 2008;73:103-112. Abstract
10. Appelbaum FR, Barrall J, Storb R, et al. Clonal cytogenetic abnormalities in patients with otherwise typical aplastic
anemia. Exp Hematol. 1987;15:1134-1139. Abstract
11. 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;107:2680-2685. Abstract
12. Cines DB, Liebman H, Stasi R. Pathobiology of secondary immune thrombocytopenia. Semin Hematol. 2009;46(1
Suppl 2):S2-S14. Full text Abstract
13. Norton A, Roberts I. Management of Evans syndrome. Br J Haematol. 2006;132:125-137. Full text Abstract
14. Seif AE, Manno CS, Sheen C, et al. Identifying autoimmune lymphoproliferative syndrome in children with Evans
syndrome: a multi-institutional study. Blood. 2010;115:2142-2145. Full text Abstract
15. 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;116:e35-e40.
Full text Abstract
16. Weinzierl EP, Arber DA. Bone marrow evaluation in new-onset pancytopenia. Hum Pathol. 2013;44:1154-1164.
Abstract
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jan 28, 2016.
BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use
35
of this content is subject to our disclaimer. BMJ Publishing Group Ltd 2015. All rights reserved.
Assessment of pancytopenia References
17. Jain A, Naniwadekar M. An etiological reappraisal of pancytopenia - largest series reported to date from a single
tertiary care teaching hospital. BMC Hematol. 2013;13:10. Abstract
REFERENCES
18. 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;70:623-627. Abstract
19. 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;103:1237-1243.
Abstract
20. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of
myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937-951. Abstract
21. Janckila AJ, Wallace JH, Yam LT. Generalized monocyte deficiency in leukaemic reticuloendotheliosis. Scand J
Haematol. 1982;29:153-160. Abstract
22. Bernasconi P, Boni M, Cavigliano PM, et al. Clinical relevance of cytogenetics in myelodysplastic syndromes. Ann N
Y Acad Sci. 2006;1089:395-410. Abstract
23. Richards SJ, Barnett D. The role of flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria in the
clinical laboratory. Clin Lab Med. 2007;27:577-590. Abstract
24. International Agranulocytosis and Aplastic Anemia Study Group. Incidence of aplastic anemia: the relevance of
diagnostic criteria. Blood. 1987;70:1718-1721. Abstract
25. Pereira RM, Velloso ER, Menezes, et al. Bone marrow findings in systemic lupus erythematosus patients with
peripheral cytopenias. Clin Rheum. 1998;17:219-222. Abstract
26. CE Allen, Yu X, Kozinetz CA, et al. Highly elevated ferritin levels and the diagnosis of hemophagocytic
lymphohistiocytosis. Pediatr Blood Cancer. 2008;50:1227-1235. Abstract
27. Zur Stadt U, Beutel K, Kolberg S, et al. Mutation spectrum in children with primary hemophagocytic
lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Hum Mutat.
2006;27:62-68. Abstract
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Assessment of pancytopenia Images
Images
IMAGES
Figure 1: Flow diagram for evaluation of pancytopenia. Abbreviations: PNH, paroxysmal nocturnal haemoglobinuria; IBMFS,
inherited bone marrow failure syndromes
From the collection of Jeff K. Davies
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IMAGES Assessment of pancytopenia Images
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Assessment of pancytopenia Disclaimer
Disclaimer
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Group Ltd ("BMJ Group") tries to ensure that the information provided is accurate and up-to-date, but we do not warrant
that it is nor do our licensors who supply certain content linked to or otherwise accessible from our content. The BMJ
Group does not advocate or endorse the use of any drug or therapy contained within nor does it diagnose patients.
Medical professionals should use their own professional judgement in using this information and caring for their patients
and the information herein should not be considered a substitute for that.
This information is not intended to cover all possible diagnosis methods, treatments, follow up, drugs and any
contraindications or side effects. In addition such standards and practices in medicine change as new data become
available, and you should consult a variety of sources. We strongly recommend that users independently verify specified
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DISCLAIMER
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Contributors:
// Authors:
// Acknowledgements:
Dr Jeffrey M. Lipton would like to gratefully acknowledge Dr Jeff K. Davies and Dr Eva C. Guinan, the previous contributors to this
monograph.
DISCLOSURES: JKD and ECG declare that they have no competing interests.
// Peer Reviewers:
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.