Results
This study involved 86 patients with BC. Among these, 48 (55.8%) were male and 38
(44.2%) were female. The male-to-female ratio was 1.3:1. Maximum number of patients
was in the age group of 40 to 69 years (55.8%), followed by 10 to 39 years and >70
years (19.8% each). The mean age of the participants was 52.2 years, with the age
ranging from 1 day to 99 years. The standard deviation of age was 31.8 years. Across
all ages in patients with BC, males outnumbered females.
Anemia with thrombocytopenia was the most common morphological type noted in 60 (69.8%)
patients, followed by anemia with leukopenia in 24 (27.9%). The least common was leukopenia,
with thrombocytopenia seen in only two (2.3%) patients.
The most common etiology of BC was found to be nonmalignant (32 cases, 37.2 %), followed
by malignant (28 cases, 37.2%), infectious (22 cases, 25.6%), and drug-induced (4
cases, 4.7 %).
The most common etiology of BC observed in the age group younger than 10 years was
infectious cases (50%), followed by malignant and drug-induced cases (25%). In the
age group 10 to 39 years, the most common etiology observed was malignancy (41.2%),
followed by infectious (29.4%). No drug-induced BC was seen in this age group. Between
40 and 69 years, the most common etiology was nonmalignant (43.7%), followed by malignant
(13%), infectious (12%), and drug-induced (4.2%). In the elderly age group, the most
common etiology was malignant (41.2%), followed by nonmalignant (35.3%), infectious
(17.6%), and drug-induced (5.9%) ([Table 1]).
Table 1
Agewise etiology distribution
|
Age
|
Malignant
|
Nonmalignant
|
Infectious
|
Drug-induced
|
|
<10 y
|
ALL B-cell (1)
|
Nil
|
Neonatal sepsis (2)
|
Burkitt's lymphoma (on chemotherapy) (1)
|
|
10–39 y
|
AML and AML (M3) (2)
Hodgkin lymphoma (2)
Adenocarcinoma of rectum (1)
CML-blast phase (1)
Olfactory neuroblastoma (1)
|
Severe aortic regurgitation (1)
Megaloblastic anemia (1)
Right parieto-occipital glioma (1)
H/o fall from height
SDH falx cerebri (1)
Alcohol hepatitis (1)
|
Viral fever (2)
Leptospirosis (1)
Viral fever (suspected infectious mononucleosis) (1)
Pulmonary embolism (1)
|
Nil
|
|
40–69 y
|
Carcinoma of left breast (2)
Carcinoma of cervix stage 2b (1)
MM (3)
AML (M5) (1)
Ovary cancer stage 3c (2)
Neuroblastoma stage 4 (1)
NHL (1)
Cutaneous T-cell lymphoma (1)
GI cancer (1)
|
Myocarditis in cardiac failure (1)
Chronic pancreatitis (1)
Chronic kidney disease (1)
Hemophilia A (1)
Vasculitis (1)
Chronic liver disease (10)
Coronary artery disease (1)
Ischemic heart disease (1)
Left femur trochanter lesion (1)
ITP (2)
TTP (1)
|
Bronchopneumonia (1)
Acute febrile illness (1)
Lower respiratory tract infection (1)
Appendicitis (1)
Sepsis with septic shock (1)
Leptospirosis (1)
Acute gastroenteritis with sepsis (1)
Viral encephalitis (1)
COVID-19 positive status (1)
Sepsis with MRSA (1)
Dengue fever (1)
Vestibular neuritis (1)
|
AML (under chemotherapy) (2)
|
|
>70 y
|
Papillary adenocarcinoma (right parietal pleura) (1)
Carcinoma of rectum (1)
Retroperitoneal abdominal mass—liposarcoma (1)
ALL (1)
ALL T-cell (1)
MM (1)
MDS (RAEB-2) monosomy 7 (1)
|
Chronic liver disease (1)
Hepatic encephalopathy (1)
Mitral valve prolapses (1)
Coronary artery disease (1)
Common bile duct calculus (1)
Splenomegaly with splenic abscess (1)
|
COVID-19 positive status (1)
Leptospirosis (1)
Right-sided pleural effusion (1)
|
Squamous cell carcinoma of the left cervical (under chemotherapy) (1)
|
Abbreviations: AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; CML,
chronic myeloid leukemia; GI, gastrointestinal; H/o, history of; ITP, immune thrombocytopenic
purpura; MDS, myelodysplastic syndrome; MM, multiple myeloma; MRSA, methicillin-resistant
Staphylococcus aureus; NHL, non-Hodgkin lymphoma; RAEB-2, refractory anemia with excess blasts type 2;
SDH, subdural hematoma; TTP, thrombotic thrombocytopenic purpura.
Anemia with thrombocytopenia was the most frequently observed morphological type of
BC in the nonmalignant etiology group, accounting for 43.3% of cases. Anemia with
leucopenia was most significant in malignant etiology, comprising 58.3% of cases.
Leukopenia with thrombocytopenia was significant equally (50%) in the infectious and
nonmalignant etiology groups ([Table 2]).
Table 2
Distribution of bicytopenia in different etiology groups
|
Bicytopenia
|
Etiology
|
|
Malignant
|
Nonmalignant
|
Infectious
|
Drug-induced
|
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
|
Anemia with thrombocytopenia
|
17
|
28.3%
|
26
|
43.3%
|
15
|
25.0%
|
2
|
3.3%
|
|
Anemia with leukopenia
|
14
|
58.3%
|
2
|
8.3%
|
6
|
25.0%
|
2
|
8.3%
|
|
Leukopenia with thrombocytopenia
|
0
|
0.0%
|
1
|
50.0%
|
1
|
50.0%
|
0
|
0.0%
|
Notes: Chi-square test = 14.381; p-value = 0.026. There is statistical significance between bicytopenia and different
etiology groups with chi-square test = 14.38; p-value < 0.05.
The most common symptom at the time of presentation was fever (41.95%), followed by
generalized weakness (30.2%), abdominal pain (25.6%), vomiting (17.4%), bleeding (14.0%),
and cough (10.5%).
Pallor and fever were the most common clinical findings (21.5% each) in malignant
etiology. Pallor (16.7%), abdominal pain (14.8%), and icterus (13%) were the most
prevalent sign in nonmalignant etiology. Fever (32.1%) and generalized weakness (15.1%)
were the most frequent clinical finding in the infectious category. The drug-induced
etiology group had pallor (40%), fever, abdominal pain, and vomiting (20% each) as
the most common sign ([Table 3]).
Table 3
Distribution of clinical features in different etiology groups
|
Clinical feature
|
Etiology
|
|
Malignant
|
Nonmalignant
|
Infectious
|
Drug-induced
|
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
|
Fever
|
14
|
21.5
|
4
|
7.4
|
17
|
32.1
|
1
|
20.0
|
|
Pallor
|
14
|
21.5
|
9
|
16.7
|
6
|
11.3
|
2
|
40.0
|
|
Icterus
|
2
|
3.1
|
7
|
13.0
|
2
|
3.8
|
0
|
0.0
|
|
Bleeding
|
7
|
10.8
|
3
|
5.6
|
1
|
1.9
|
0
|
0.0
|
|
Lymphadenopathy
|
4
|
6.2
|
1
|
1.9
|
1
|
1.9
|
0
|
0.0
|
|
Hepatomegaly
|
2
|
3.1
|
5
|
9.3
|
0
|
0.0
|
0
|
0.0
|
|
Splenomegaly
|
1
|
1.5
|
3
|
5.6
|
0
|
0.0
|
0
|
0.0
|
|
Abdominal pain
|
6
|
9.2
|
8
|
14.8
|
7
|
13.2
|
1
|
20.0
|
|
Vomiting
|
4
|
6.2
|
6
|
11.1
|
4
|
7.5
|
1
|
20.0
|
|
Cough
|
0
|
0.0
|
1
|
1.9
|
7
|
13.2
|
0
|
0.0
|
|
General weakness
|
11
|
16.9
|
7
|
13.0
|
8
|
15.1
|
0
|
0.0
|
|
Total
|
65
|
100.0%
|
54
|
100.0%
|
53
|
100.0%
|
5
|
100.0%
|
Discussion
There is a broad spectrum of etiology of BC ranging from malignancies to nonmalignant
conditions, infections, and following exposure to certain drugs. Only a few studies
in the literature have evaluated the clinical variables and etiological factors of
BC in different age groups. Considering these facts, data from bicytopenic patients
were collected for the first time in southern region of India.
In India, BC is most prevalent in adults, whereas the prevalence of BC in children
is slightly lower than in adults.[9] In our study, BC was seen most frequently in adults between 40 and 69 years of age
(55.8%), followed by elderly >70 years (19.8%) and 10 to 39 years (19.8%), while children
<10 years of age (4.7%) were the least affected.[4] The findings are comparable to the study conducted by Singh et al, where BC was
most frequently observed in adults (55.5%), followed by children (17.25%), elderly
individuals (11.25%), and teenagers and infants (8% each).[3] According to a study in Pune, the commonest age group affected was in the third
and fourth decades.[4] Dagdia et al reported that 77.33% of BC were in patients between 21 and 80 years.[2] In a study of BC in children conducted by Katoch et al, the commonest age group
affected (42%) was between 11 and 15 years.[8] These variations may be attributed to differences in the population being studied,
geographic distributions, and periods of observations. Though the frequency of BC
in children is relatively low, they are not entirely spared.
In India, BC is more common in males than females.[3]
[5] In our study, the majority were male (55.8%) with a male-to-female ratio of 1.3:1.
This finding is similar to most of the available literature in India. Foreign studies
suggest that gender distribution is not different from the Indian scenario. Sarbay
reported that 56.2% of BC patients were males.[6] Kato et al from Japan reported that 70.7% of study subjects were male.[9] The higher incidence of BC in males may be due to male preponderance in malignancies,
personal habits such as alcohol abuse, and relatively more outdoor exposure to infections
than females.
The Pattern of Bicytopenia in Various Groups
In the present study, the most prevalent type of BC was found to be anemia with thrombocytopenia
(69.8%), followed by anemia with leukopenia (27.9%) and leukopenia with thrombocytopenia
(2.3%). These findings align with the results reported by Naseem et al, who also observed
that anemia with thrombocytopenia was the most common type of BC (77.5%), followed
by anemia with leukopenia (17.3%) and leukopenia with thrombocytopenia (5.5%).[5]
Malignant conditions such as acute leukemia presented with anemia and thrombocytopenia
in 78.6% of cases. It is well known that infiltration of bone marrow with immature
progenitor cells leads to relative suppression of erythroid and megakaryocyte series,
resulting in peripheral blood anemia with thrombocytopenia.
Anemia with leukopenia was most common (27.9%) in malignant etiology. Nine cases were
seen in various organ malignancies of the breast, cervix, ovary, and colorectum. This
may be due to decreased immunity in these cancer patients. Hematological malignancies
such as subleukemic acute myeloid leukemia (AML), Hodgkin lymphoma, and non-Hodgkin
lymphoma also presented with anemia with leucopenia.
Leukopenia with thrombocytopenia was equally prevalent (50% each) in nonmalignant
and infectious etiologies. The only infectious etiology in this group was dengue fever.
Dengue virus causes the destruction or suppression of myeloid progenitor cells, which
leads to leukopenia and peripheral destruction of platelets or destruction of bone
marrow megakaryocytes by the virus, resulting in decreased platelet count.[10]
Microcytic hypochromic anemia was the most common morphological subtype of anemia
(41.5%) in malignant etiology. Dimorphic and macrocytic anemia (43.3%) were common
in nonmalignant and normocytic normochromic anemia (50%) in infectious etiology.
Macrocytic anemia in chronic liver disease (CLD) may be caused by increased cholesterol
deposition on the membranes of circulating red blood cells. This deposition effectively
expands the erythrocyte's surface area. Peripheral smear shows nonmegaloblastic macrocytosis
displaying round macrocytes characteristic of CLD.[11] Viral or bacterial infections can also result in anemia through mechanisms such
as mild idiopathic hemolysis and marrow inhibition.[12]
Bone Marrow Examination
In our study, a bone marrow examination was performed on eight patients with BC. It
was done in three cases of multiple myeloma, two cases of immune thrombocytopenic
purpura (ITP), one case of Burkitt's lymphoma, one case of AML (M5), and one case
of chronic myeloid leukemia—blast phase.
Few studies of BC in adults and children have been conducted in bone marrow examination.
In a study conducted by Dagdia et al, they reported that the most common finding in
bone marrow examination was megaloblastic anemia (29.3%) observed in all age groups
except between 61 and 80 years, followed by aplastic anemia, AML, and myelodysplastic
syndrome (22.22%) in 61 to 80 years.[2] A study by Katoch et al in children showed that bone marrow examination helped diagnose
six cases of acute lymphoblastic leukemia (ALL) and one case of AML. It also helped
in diagnosing nonmalignant conditions such as aplastic anemia (two cases), megaloblastic
anemia (two cases), ITP and iron deficiency anemia (one case each).[8]
Bone marrow examination is indicated in various neoplastic and nonneoplastic diseases.
In cases of leukemia, further studies such as fluorescence in situ hybridization can
be done on bone marrow samples for subtyping. It is necessary to diagnose and initiate
the proper treatment, management, and prognostic purposes.
Symptoms and Signs
In our study, the most common symptom reported at the time of presentation was fever
(41.95%), followed by generalized weakness (30.2%), abdominal pain (25.6%), vomiting
(17.4%), bleeding (14.0%), and cough (10.5%). Fever was observed predominantly in
infectious etiology (47.2%). These findings are similar to the study done by Katoch
et al.[8]
Fever is a physiological reaction to infectious, inflammatory, and autoimmune diseases.
It involves the secretion of chemical mediators, which activate the hypothalamic thermoregulatory
center and elevate body temperature.[13]
Pallor was the most prevalent sign (36.0%), followed by icterus (12.8%), hepatomegaly
(8.1%), lymphadenopathy (7.0%), and splenomegaly (4.7%). Pallor was most common in
malignant conditions (21.5%) such as multiple myeloma, ALL, adenocarcinoma of the
rectum, ovarian cancer, and cutaneous T cell lymphoma, which had anemia and thrombocytopenia.
Icterus (13%), hepatomegaly (9.3%), and splenomegaly (5.6%) were common signs in nonmalignant
conditions such as chronic liver disease, chronic pancreatitis, and splenomegaly with
splenic abscess. Lymphadenopathy was a common sign in malignant conditions such as
Hodgkin lymphoma, non-Hodgkin lymphoma, carcinoma of the left breast, and cutaneous
T cell lymphoma.
Katoch et al, in their study, also reported that pallor (86%) was the most common
sign, followed by hepatomegaly (64%), lymphadenopathy (60%), and splenomegaly (58%).[8] In a study done by Thakur et al, hepatomegaly was found in 14.8% of bicytopenic
patients, splenomegaly (9.6%), whereas lymphadenopathy was found in 12.6% of bicytopenic
patients.[4]
Extramedullary infiltration of blasts causes splenomegaly, lymph node enlargement,
gum involvement, and diffuse skin infiltration in AML.[14]
Bleeding manifestations are due to thrombocytopenia, fatigue, and weakness due to
anemia. Fever is due to increased susceptibility to infections due to decreased levels
of neutrophils. Signs such as hepatosplenomegaly and lymphadenopathy are attributed
to malignant etiology such as leukemia.
Etiologies
Nonmalignant etiology emerged as the predominant cause of BC in our study (37.2%),
followed by malignant conditions (32.5%), infectious cases (25.6%), and drug-induced
cases (4.7%). Few studies of BC have been done in children and few in adults.
A study conducted by Thakur et al in adult patients presenting with BC reported that
the most common etiology was infectious cases (77.8%), followed by nonmalignant (17%),
drugs (3%), and malignant (2.2%).[4]
These findings diverge from a study conducted by Naseem et al, where malignant etiology
was reported as the most common cause of BC in children (69.5%), followed by nonmalignant
cases (18.4%) and nonspecific causes (12.1%).[5]
The variations could be because the present study included all age groups who were
presented with BC.
Nonmalignant Conditions
Among the nonmalignant cases, chronic alcoholic liver disease was found to be the
most common nonmalignant cause, accounting for 12.8% of the cases, followed by ITP
and coronary artery disease (2.3% each). These patients had anemia with thrombocytopenia.
A study conducted by Vijay et al also found chronic alcoholic liver disease as the
predominant nonmalignant cause of BC.[15]
CLD leads to progressive liver damage, impacting the synthesis of proteins and clotting
factors, detoxification processes, and bile excretion. This deterioration results
in hematological complications such as cytopenias (BC) and coagulation irregularities.
Conditions such as megaloblastic anemia, iron deficiency anemia, double deficiency
anemia, aplastic anemia, marrow failure, and spleen cell sequestration can contribute
to cytopenias in individuals with CLD. Furthermore, diminished production of thrombopoietin
by the liver is a factor in decreased platelet counts.[16]
Singh et al conducted a study that revealed alcoholic liver disease as the second
most prevalent nonmalignant cause of BC, following ITP.[3]
CLD is not cited as a cause in studies on BC in children.[3] In our study, a maximum number of patients were in the age group between 40 and
69 years, which could be the reason for increased cases of alcoholic liver disease.
There were two cases of ITP presented with BC in our study. Their peripheral smear
showed anemia (dimorphic anemia) with thrombocytopenia. These women were 43 and 53
years old and presented with bleeding, fever, and overall weakness. Bone marrow aspiration
showed hypercellular marrow with both erythroid and megakaryocytic hyperplasia ([Fig. 1]).
Fig. 1 Bone marrow aspiration showing increase in megakaryocytes (thick arrow), ×40, Leishman's
stain.
Naseem et al reported that the most common etiology of BC was ITP (5.2%).[5]
One case of chronic kidney disease (CKD) was encountered in this study. His peripheral
smear showed microcytic hypochromic anemia with leucopenia. CKD causes BC, most commonly
anemia, and leucopenia, via complex mechanisms. CKD-related kidney damage reduces
erythropoietin production, leading to anemia due to decreased red blood cell formation.
Concurrently, accumulated uremic toxins affect bone marrow function, impairing red
and white blood cells production and resulting in leucopenia.[17]
Megaloblastic anemia causes anemia and low platelet count by hampering DNA synthesis
due to vitamin B12 or folate deficiencies. This disruption affects the bone marrow's
red blood cells and platelet maturation, producing enlarged immature red cells (megaloblasts),
causing anemia, and impeding platelet formation. The impaired DNA replication alters
platelet production, reducing count alongside anemia.[18] We had one case of megaloblastic anemia who had macrocytic anemia with thrombocytopenia
([Fig. 2]). One case of splenomegaly with splenic abscess was seen in an 87-year-old man.
Fig. 2 Peripheral blood smear showing macrocyte (black arrow), ×100, Leishman's stain.
Malignant Conditions
In the current study, malignant conditions (32.5%) were further subdivided into hematological
causes (16, 51.6%) and nonhematological causes (15, 48.4%). The most common hematological
malignant etiology of BC was multiple myeloma (25%), followed by AML (18.8%) and Hodgkin
lymphoma (12.5%). The most common nonhematological malignant etiology of BC was carcinoma
of the breast and ovarian cancer (16.7% each).
In a study conducted in Belgaum, the most frequent malignant etiology of BC was observed
to be AML, with a prevalence of 4.75%, followed by ALL with a prevalence of 2.5%.[3] Conversely, another study conducted in Chandigarh on BC/pancytopenia in a pediatric
population reported that acute leukemia was the most common cause, accounting for
66.9% of cases.[5]
BC in multiple myeloma stems primarily from bone marrow infiltration by malignant
plasma cells, disrupting the normal production of red blood cells and platelets. Multiple
myeloma patients presented with anemia and thrombocytopenia. Plasma cells were increased
(88%) in bone marrow aspiration. ([Fig. 3]).
Fig. 3 Bone marrow aspiration showing increase in plasma cells (thick arrow), ×100, Leishman's
stain.
BC in AML commonly occurs due to bone marrow infiltration by rapidly proliferating
leukemic blasts, suppressing the normal production of red blood cells and platelets.
In the current study, AML patients presented with anemia and thrombocytopenia. The
myeloblasts ranged from 10 to more than 20% in peripheral blood smears, varying between
cases, while they exceeded 20% in bone marrow smears. Myeloblast has enlarged irregular
round to oval nuclei, fine chromatin, three to five nucleoli, and basophilic agranular
cytoplasm. A few can show Auer rods ([Fig. 4]).
Fig. 4 Bone marrow aspiration showing myeloblasts (black arrow), ×100, Leishman's stain.
Ours is a tertiary care hospital; hence, the number of patients with malignancies
visiting our center is also high on a day-to-day basis, which could have led to increased
cases of malignant etiology in our study.
Infectious Conditions
The present study identified infectious etiology as the third most prevalent cause
of BC, comprising 25.6% of the cases.
Leptospirosis was the most prevalent infectious etiology, accounting for 3.5% of the
cases, followed by neonatal sepsis and COVID-19 infection (2.3% each). All the cases
of leptospirosis presented with anemia and thrombocytopenia.
Leptospirosis causes anemia with thrombocytopenia by triggering bone marrow suppression
and immune-mediated destruction of red blood cells and platelets.
Infectious etiology was the most common cause of BC, accounting for 61.8% of the cases
in a study by Thakur et al, who reported dengue fever as the most common infectious
cause of BC.[4] In the present study, one case of dengue fever presented as leukopenia with thrombocytopenia.
Serology was positive for nonstructural protein 1 antigen. Atypical lymphocytes were
found in the peripheral smear ([Fig. 5]).
Fig. 5 Peripheral smear showing atypical lymphocyte in dengue fever (arrow), ×100, Leishman's
stain.
Drug-Induced
The drug-induced etiology showed the least number of cases causing BC in the current
study (4.7%). The most common drug-induced etiology was chemotherapy for AML (2.3%)
with arasid and daunorubicin injection, followed by chemotherapy for squamous cell
carcinoma of the oral cavity (1.2%) and chemotherapy for Burkitt's lymphoma (1.2%).
Chemotherapy for AML presented anemia with thrombocytopenia, whereas the latter two
cases presented with anemia with leukopenia.
Singh et al found retroviral disease patients and certain nonhematological malignancies
such as lung carcinoma and cervical carcinoma on chemotherapy as the most frequent
cause of drug-induced BC.
Drugs which cause BC are antiretroviral drugs such as zidovudine and efavirenz, antipsychotic
drugs, benzodiazepine abuse, antidepressants, and anti-epileptic drugs.[3] Certain drugs cause isolated thrombocytopenia. Drugs such as quinine, cephalosporins,
L-Dopa cause thrombocytopenia by binding to antibody and platelet membrane glycoprotein,
promoting antibody response and formation of autoantibodies, respectively.[19]
Many studies have been done on BC only in children or adults separately. Our study
covers the etiological spectrum of BC across all age groups. It also categorizes the
malignant causes into hematological and nonhematological malignant causes, offering
better insights to existing literature.
Limitations of this study included a restricted timeline for sample collection, resulting
in a small sample size. Not all leukemic patients' samples were subjected to advanced
tests such as flow cytometry and cytogenetics due to financial constraints.
