C H A P T E R

Pancytopenia: Clinical approach

95 Ajai Kumar Garg, AK Agarwal, GD Sharma

INTRODUCTION normal adult marrow produces about 170x109 RBC,

Pancytopenia is a common haematological condition often 100x109 neutrophils, and 200x109 platelets daily. Defects
encountered in day to day clinical practice. It is defined in the stem cells or in the stroma or microenvironment
as a decrease in all the three cell lines of blood viz., red of bone marrow can lead to bone marrow failure and
blood cells, leucocytes, and platelets. Many diseases affect pancytopenia.
production of these cells by bone marrow resulting into Pancytopenia is not a disease by itself but a triad of
pancytopenia i.e., simultaneous presence of anaemia, haematological finding that can result from a number of
leucopenia, and thrombocytopenia. Pancytopenia is disease processes (Tables 1 & 2). It can be a feature of many
defined as haemoglobin of < 9 gm/dl, WBC < 4,000/cmm, serious and life threatening illnesses like drug induced
and platelets < 100,000/cmm. Severe pancytopenia is bone marrow hypoplasia, fatal bone marrow aplasia, and
defined as absolute neutrophil count < 500/cmm, platelet leukaemias. It can result from failure of production of
count < 20,000/cmm, and corrected reticulocyte count < stem cells in bone marrow, infiltration of bone marrow
1%. by malignant cells or fibrosis, immune mediated bone
Presenting symptoms of pancytopenia may be attributable marrow suppression, ineffective erythropoiesis and
to anaemia, leucopenia, and/or thrombocytopenia. dysplasia, peripheral sequestration of blood cells by
Anaemia may present with fatigue, breathlessness, and overactive reticuloendothelial system, and immune or
cardiac symptoms. Neutropenia may present with febrile non-immune mediated increased destruction of blood
illness due to increased susceptibility to infections. cells. Marrow damage may be caused by infiltration
Patients with thrombocytopenia may present with of marrow with tumour or fibrosis that crowds normal
mucocutaneous bleed or bruising. Pancytopenia should marrow cells. Tumour or fibrosis that infiltrates the
be suspected on clinical grounds in any patient presenting marrow may originate in the marrow as in leukaemia
with unexplained anaemia, prolonged fever and bleeding or myelofibrosis or be secondary to process originating
tendency. The severity of pancytopenia and underlying outside marrow as in metastatic cancer or myelophthisis.
aetiology determine the management and prognosis. Incidence of various disorders causing pancytopenia
Pancytopenia usually presents with the clinical sign varies according to geographical distribution and genetic
and symptoms of bone marrow failure such as pallor, mutations. Main causes of pancytopenia in our country
easy fatigability, dyspnoea, bleeding or bruising, and are megaloblastic anaemia due to nutritional deficiencies,
increased tendency to infection. As platelets have shortest hypersplenism (congestive splenomegaly, malaria,
half life, platelet count is first to be affected leading to and leishmaniasis), aplastic anaemia, myelodysplastic
thrombocytopenia. Mucocutaneous bleed is typical syndrome, subleukaemic leukaemias, military
manifestation of decreased platelet count with petechial tuberculosis, multiple myeloma, paroxysmal nocturnal
haemorrhages in the skin and mucous membrane. haemoglobinuria.
Epistaxis, haematuria, gastrointestinal bleeding, According to a study of 200 cases of pancytopenia
menorrhagia, and rarely intracranial bleeding are the conducted by Khunger et al at a large general hospital
presenting features of thrombocytopenia. Anaemia in North India, the commonest cause found was
develops slowly because RBC has longest half life. Early megaloblastic anaemia seen in 72% cases, followed
manifestation of neutropenia is often a sore throat, or chest by aplastic anaemia (14%). The other causes included
or soft tissue infection with poor response to antibiotics. subleukaemic leukaemia (10 cases), myelodysplastic
Patients with pancytopenia may develop overwhelming syndrome (4 cases), hypersplenism due to kala azar
sepsis without any focal sign of infection, with malaise (4 cases), hypersplenism due to malaria (2 cases), Non-
and fever being the only clinical features. Hodgkin’s lymphoma, myelofibrosis, multiple myeloma
(2 cases each), Waldenstrom macroglobulinaemia and
AETIOLOGY OF PANCYTOPENIA
disseminated tuberculosis (1 case each). In another
Normal marrow has tremendous capacity to increase
prospective study of 104 pancytopenic patients conducted
the output of peripheral blood cells whenever necessary
by Gayatri and Rao at a teaching institute in South India for
with the help of growth factors and cytokines. All the
a period of two years, commonest cause of pancytopenia
peripheral cells arise from common progenitor pluripotent
was megaloblastosis (74%) followed by aplastic anaemia
cells having enormous capacity of self renewal. The
(18%).
In another prospective study of 250 cases of pancytopenia subcontinent. Vitamin B12 deficiency may also cause 451
conducted by Jain and Naniwadekar at a tertiary care subacute combined degeneration of cord and psychiatric
hospital in Maharashtra hypersplenism (29.2%), infections illness (megaloblastic madness). The degree of bone
(25.6%), myelosuppression (16.8%), megaloblastosis marrow suppression is inversely related to presence and
(13.2%), and hypoplastic/aplastic anaemia (4.8%) were severity of neurological dysfunction. The coexistence of
found to be the common causes of pancytopenia. In this significant anaemia and neurological deficit is thought to
study a male preponderance was observed, male to female be rare.
ratio being 2.6:1 and majority of cases were encountered
in third and fourth decade of life. In an analysis of 166 Hypersplenism
cases of pancytopenia conducted by Kumar et al at two Hypersplenism is characterized by splenomegaly,
tertiary care hematology centers where patients receiving cytopenia(s), normal or hyperplastic bone marrow,
myelotoxic chemotherapy or those with leukaemic cells and a response to splenectomy. In hypersplenism
in peripheral blood smears were excluded from the there is peripheral pooling and destruction of cells

CHAPTER 95
study, it was observed that aplastic anaemia (49 cases) in enlarged spleen resulting in pancytopenia. Causes
was most common cause followed by megaloblastic of hypersplenism include congestive splenomegaly
anaemia (37cases), aleukaemic leukaemia or lymphoma (cirrhosis, congestive heart failure), malaria, hyperreactive
(30 cases), and hypersplenism (19 cases). Megaloblastosis malarial splenomegaly, leishmaniasis, thalassaemia,
was not commonest cause of pancytopenia in these series and Hodgkin’s disease. Hypersplenism can rarely be
probably because many cases of megaloblastic anaemia idiopathic.
need not be referred to a tertiary care centre and could Infections
easily be treated at general hospitals. Haematologic abnormalities have been frequently
observed in patients with HIV infection. Pancytopenia is
OVERVIEW OF COMMON CAUSES OF PANCYTOPENIA
usually seen in advanced stage of HIV infection. Aetiology
Megaloblastic anaemia (Tables 3 & 4) of pancytopenia in advanced HIV stage is multi-factorial
Megaloblastic haematopoiesis is a hypercellular
bone marrow failure due to deficiency of vitamin B12
(cobalamin) and folate. These nutrients have important Table 2: Causes of pancytopenia with hypocellular marrow
role in synthesis of DNA. Megaloblastic anaemia is a Acquired aplastic anemia
predominant cause of pancytopenia in India because Congenital aplastic anaemia (Fanconi’s anaemia)
of high prevalence of nutritional anaemia in Indian
Some myelodysplasias
Acute myeloid leukaemia
Table 1: Causes of pancytopenia with cellular bone marrow
Acute lymphoid leukaemia
Primary bone marrow Secondary to systemic disease
disease Lymphoma of bone marrow
Myelodysplasia Vitamin B12 deficiency, folate
deficiency Table 3: Causes of Vitamin B12 deficiency
Paroxysmal nocturnal Hypersplenism Food Decreased consumption-vegan diet,
haemoglobinuria cobalamin malabsorption (common in
elderly)
Myelophthisis Alcoholism
Stomach Pernicious anaemia, atrophic gastritis,
Myelofibrosis Sepsis, enteric fever gastrectomy, gastric bypass, H. pylori
Subleukaemic HIV infection, hepatitis B, infection, Zollinger-Ellison syndrome
leukaemia hepatitis C, Ebstein-Barr virus, Intestine Chronic pancreatitis, tropical sprue, celiac
cytomegalovirus disease, ileal resection, fish tapeworm
Bone marrow Malaria, leishmaniasis, infestation, bacterial overgrowth
lymphoma filariasis syndrome, HIV infection
Hairy cell leukaemia Systemic lupus erythematosus, Drugs Metformin, Proton pump inhibitors, H 2
sarcoidosis blockers

Table 4: Causes of folate deficiency

Nutritional deficiency Dietary deficiency
Increased requirements Infancy and childhood, pregnancy, malignancy, chronic haemolytic anaemia, chronic
exfoliative dermatitis, chronic inflammatory disorders (tuberculosis, rheumatoid
arthritis, Crohn’s disease), CHF, chronic liver disease, haemodialysis, homocystinuria
Malabsorption Tropical and non-tropical sprue, gluten sensitive enteropathy
Drugs Antiepileptic drugs, methotrexate, pyrimethamine, alcohol
Congenital Abnormalities of folate metabolism
 452 in nature and includes high viral load, use of antiretroviral Acute leukaemias
therapy, and presence of acute or chronic opportunistic Acute myeloid leukaemia occurs in all age group but
infection. Viral hepatitis has been known to cause predominantly in older adults. Acute lymphoblastic
transient pancytopenia during the course of illness and leukaemia is the most common acute leukaemia in
has also been associated with aplastic anaemia. Hepatitis childhood. Clinical history and symptoms usually indicate
associated with pancytopenia and aplastic anaemia is bone marrow failure. These include fatigue, dyspnoea,
usually fatal. Whereas hepatitis B and hepatitis C are dizziness, bleeding, easy bruising, and recurrent
common causes; Epstein-Barr virus, cytomegalovirus, infections. Cytogenetic abnormalities are prognostically
and rarely hepatitis A and dengue virus can also cause important and affect patient management. In all cases
pancytopenia. Mild blood count depression is common in of severe pancytopenia (symptomatic anaemia, WBC <
course of many viral and bacterial infections but resolves 500/mcL, and platelets < 20,000/mcL) investigations are
with the resolution of infection. Sepsis and enteric mandatory within first 24-48 hrs. Supportive therapy
HAEMATOLOGY

fever continue to be important public health problems with RBC, platelets, and broad spectrum antibiotics may
in India and have been associated with pancytopenia be initiated before underlying cause has been ascertained.
which has been attributed to bone marrow suppression,
disseminated intravascular coagulation, and infection Myelodysplastic syndrome
associated haemophagocytic syndrome. Tuberculosis Myelodysplastic syndromes (MDS) are the common
is a common disease in India. Disseminated miliary haematological diseases characterized by cytopenias
tuberculosis is known to cause pancytopenia. Although associated with abnormal appearing cellular marrow
pancytopenia is a rare presentation of tuberculosis, it producing ineffective red blood cells. The incidence of
should always be considered in patients presenting with MDS increases with advancing age. Median age at disease
pancytopenia, unexplained pyrexia and weight loss. onset is 70 years with only about 10% of the patients below
Both tuberculous bacilli and anti-tuberculous therapy 50 years. MDS are diseases of haematopoietic stem cells.
have been implicated in pathogenesis of pancytopenia. They are characterized by disturbance of differentiation
Wuchereria bancrofti is an endemic filarial nematode spread and maturation, and by changes in the bone marrow
by a mosquito vector. The clinical manifestations vary stroma. MDS are accompanied not only by reducing
from asymptomatic microfilaraemeia to lymphoedema. blood cell counts but also with an increased risk (20-25%)
Cases of microfilaria in bone marrow aspirate presenting of developing acute myeloid leukaemia. The disease
as pancytopenia in peripheral blood have been reported. course varies greatly from patient to patient, with median
Though, aetiopathological correlation of pancytopenia survival time from few months to years.
with microfilaria infection is not clear. Systemic lupus erythematosus (SLE)
Aplastic anaemia Haematologic abnormalities such as anaemia, leucopenia,
Aplastic anaemia is defined as pancytopenia with and thrombocytopenia secondary to peripheral destruction
hypocellular marrow in absence of abnormal infiltrate are commonly seen in SLE. Most frequent haematologic
or increased fibrosis. It is a normocytic normochromic manifestation of SLE is normocytic and normochromic
anaemia that results from a loss of blood cell precursors, anaemia. Leukopenia is also common and almost always
causing hypoplasia of bone marrow leading to consists of lymphopenia and not granulocytopenia.
pancytopenia. Severe aplastic anaemia is defined as a bone Thrombocytopenia may be a recurring problem in SLE.
marrow cellularity < 25% with at least two of the three Cytopenias from autoimmune myelofibrosis are also
criteria i.e., neutrophils < 500/mcL, platelets < 20,000/mcL, uncommonly seen in SLE.
and reticulocyte count < 20,000/mcL. It is a potentially life Idiopathic cytopenia of undetermined significance
threatening failure of bone marrow. Most cases of aplastic Idiopathic cytopenia of undetermined significance
anaemia are acquired and T-cell mediated autoimmune (ICUS) is a recently proposed provisional diagnosis
disease. Triggering factors may include drugs, viruses, that recognizes patients who present with cytopenias
and toxins but most cases are idiopathic. In some cases of undetermined aetiology. Diagnostic criteria for ICUS
radiation, drugs, toxic chemicals and viruses induce include: i) persistent cytopenia for 6 months (Hb < 11mg/
depletion of haematopoietic stem cells by direct toxicity. dl, neutrophil < 1.5x109 /L, and platelets < 100x109/L); ii)
Paroxysmal nocturnal haemoglobinuria (PNH) No morphologic feature of myelodysplasia; iii) normal
PNH is an acquired chronic haemolytic anaemia chromosome analysis; and iv) A detailed clinical history
characterized by persistent intravascular haemolysis with and investigation that excludes other secondary causes
recurrent exacerbations due to activation of complement of cytopenias. The diagnosis of ICUS should only be
C. In addition to haemolysis, there is often pancytopenia established when all possible differential diagnosis have
and a risk of venous thrombosis. Haemolysis in PNH been excluded. The term Idiopathic fatal pancytopenia
is due to an intrinsic abnormality of the red cell, which has been suggested for ICUS because it is a fatal disease
makes it sensitive to activated complement C. Diagnostic with no definite cause.
gold standard of PNH is flow cytometry which can be Drug Induced pancytopenia (Table 5)
carried out on granulocytes as well as on RBC. A bimodal Drugs are the common cause of pancytopenia. Drug
distribution of cells with a discrete population that is induced pancytopenia can be dose dependent or immune
CD59 and CD55 negative is diagnostic of PNH.
 megaloblastic anaemia. In addition liver function 453
Table 5: Common drugs causing pancytopenia
test, viral markers for hepatitis, coagulation profile,
a. By bone marrow suppression: Cytotoxic drugs fibrinogen, D-dimer, serum B12, folate levels, HIV
b. By dose dependent effect: Chloramphenicol serology, antinuclear antibodies (ANA) should be done.
Serum ferritin levels should also be assessed. Low levels
c. By immune mediated idiosyncratic reaction of serum ferritin along with low serum B12 and/or folate
NSAIDS, chloremphenicol, sulphonamide, levels may indicate mixed anaemia/pancytopenia.
phenothiazines, thiazides, anti-thyroid drugs,
Peripheral blood smear provides important information
anti-epileptics, anti-diabetic drugs, colchicine,
in pancytopenia and it should always be done prior
azathioprine
to transfusion of blood. Blood smear may reveal
mediated (idiosyncratic). Chloramphenicol can cause polychromasia—red cells that are slightly larger than
pancytopenia by both the mechanisms. Azathioprine, normal and greyish blue in colour. These cells are

CHAPTER 95
an immunosuppressive drug used for treatment of reticulocytes that have been prematurely released from
various diseases, usually causes leucopenia and rarely the bone marrow. These cells may appear in circulation
pancytopenia. due to architectural damage of the bone marrow caused
by fibrosis or malignant cell infiltration.
CONGENITAL CAUSES OF PANCYTOPENIA
Bone marrow examination is almost always indicated
Fanconi’s anaemia is an autosomal recessive disorder
in cases of pancytopenia unless the cause is otherwise
and manifests as congenital developmental anomaly,
apparent (e.g., chronic liver disease with portal
progressive pancytopenia, and an increased risk of
hypertension, deficiency of vitamin B12 or folate). In
malignancy. Patients typically have short stature, café
megaloblastic anaemia bone marrow shows megaloblastic
au lait spots, and anomalies involving thumb, radius,
erythroid hyperplasia, sieved nuclear chromatin,
and genitourinary tract. Dyskeratosis congenita is
asynchronous nuclear maturation, bluish cytoplasm with
characterized by mucous membrane leukoplakia,
cytoplasmic blebs. Giant metamyelocytes and band forms
dystrophic nails, reticular hyperpigmentation, and
are predominant in granulocyte series. Bone marrow
development of aplastic anaemia during childhood.
in aplastic anaemia is hypocellular with suppression of
APPROACH TO A CASE OF PANCYTOPENIA erythropoiesis, myelopoiesis, and megakaryopoiesis with
Evaluation of pancytopenia requires a careful history relative lymphoplasmacytosis. In acute leukaemias, bone
and physical examination. The causes of pancytopenia marrow is hypercellular with reduced erythroid and
are diverse. Attention must be paid to history of the megakaryocytic series and majority of cells are myeloblast
patient and the family. Nutritional history, drug history or lymphoblast. Bone marrow aspiration in AML shows
and history of alcohol intake should always be assessed. myeloblast with Auer rods.
History suggestive of previous pancytopenia, aplastic
anaemia, inherited bone marrow failure syndrome,
ABSOLUTE RETICULOCYTE COUNT
An accurate reticulocyte count is the key to initial
repeated early foetal loss, cancer, liver disease, metabolic
evaluation of pancytopenia. Normally, reticulocytes are
disorders, or connective tissue disorder is important.
the red cells that have been recently released from the
Cytotoxic chemotherapy and radiotherapy are important
bone marrow. Normal reticulocyte count ranges from
cause of transient pancytopenia. History of weight
1-2% and reflects the daily replacement of 0.8-1% of the
loss and anorexia may suggest underlying infection or
circulating RBC population. Reticulocyte count provides
malignancy. Recurrent oral ulcers and chronic diarrhoea
a reliable measure of RBC production. Reticulocyte count
may point towards HIV infection. Recurrent oral ulcers,
and absolute reticulocyte count (ARC) should be done
malar rash and joint pain may suggest SLE. Bone pain and
on day one along with CBC in order to avoid therapy
loss of height indicate multiple myeloma.
related changes in reticulocyte count particularly with
A thorough physical examination is of paramount nutritional anaemia. Absolute reticulocyte count (ARC) is
importance in evaluation of pancytopenia. It should a calculated index derived from the product of reticulocyte
include assessment of jaundice, clubbing of fingers, count percentage and RBC count (Normal; Male: 4.32-5.72
lymphadenopathy and splenomegaly (underlying million/cmm, Female: 3.90-5.03 million/cmm). ARC is a
infection, infectious mononucelosis, lymphoproliferative marker of red cell production by bone marrow. It plays
disorder, and malignancy), loss of height (suggestive of important role in establishing the cause of pancytopenia
multiple myeloma), malar rash, retinal haemorrhage, oral and helps in distinguishing between hypoproliferative
petechiae, gingival hyperplasia, stomatitis or cheilitis, and hyperproliferative anaemias. Normal range of
oropharyngeal candidiasis, RUQ abdominal tenderness, absolute reticulocyte count is 50,000-100,000/cmm. All
signs of chronic liver disease. cases of pancytopenia with very low ARC (< 25,000/
Laboratory evaluation: A routine complete blood cmm) should be examined by bone marrow aspiration
count (CBC) is required as a part of initial evaluation for aplastic anaemia. All cases of pancytopenia with high
of pancytopenia. CBC should include red cell indices, ARC (> 100,000/cmm) should also be evaluated by bone
peripheral blood film, reticulocytes count and absolute marrow aspiration unless there is a history suggestive of
reticulocyte count. A very high MCV (>110fl) indicates sepsis or malaria. Pancytopenia with ARC 25,000-50,000/
 Flow diagram for evaluation of pancytopenia

454
Pancytopenia

Peripheral blood smear and reticulocyte count

Bone marrow aspiration,

Liver function test, coagulation profile
Trephine biopsy
Vitamin B12, folate levels
HAEMATOLOGY

Viral serology (HIV, HBV, HCV, EBV, CMV)

Autoimmune profile Bone marrow cytogenetics and

immunophenotyping

Specific investigations

Fig. 1: Flow diagram for Evaluation of Pancytopenia

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