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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 6  |  Issue : 4  |  Page : 309-315

Complete clinicopathological profile and etiological spectrum of pancytopenia in adult patients attending a tertiary care referral center in Eastern India


1 Department of Pathology, Medical College and Hospital, Kolkata, West Bengal, India
2 Department of Lab Services, Health World Hospitals, Durgapur, West Bengal, India

Date of Submission14-May-2020
Date of Acceptance06-Oct-2020
Date of Web Publication24-Dec-2020

Correspondence Address:
Dr. Sankha Subhra Sinha
Health World Hospitals, Plot No. C-49, Commercial Area, City Centre, Durgapur - 713 216, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJAM.IJAM_55_20

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  Abstract 


Introduction: Pancytopenia is a common hematological condition manifesting as a simultaneous decrease in formed elements of blood-red blood cell, white blood cell, and platelets. It happens in many illnesses, ranging from simple drug-induced bone marrow hypoplasia, megaloblastic anemia to fatal bone marrow aplasias and leukemias. Identifying the correct etiology and clinicopathological spectrum of pancytopenia helps in implementing timely and appropriate treatment. Hence, this study was undertaken for profiling pancytopenia and we chose to focus on adult patient only.
Materials and Methods: The present study was an observational, cross-sectional study conducted at a tertiary care referral center in Kolkata which included 91 cases of pancytopenia over a period of 2 years. Cases were of both sexes and age >20 years who were not on any kind of drug therapy. Cases were evaluated clinically and with complete set of relevant pathological parameters.
Results: In our study, the most common etiology was aplastic anemia (24.2%), followed by myelodysplastic syndrome (17.6%) and acute leukemia (14.3%). The most common age range being 21–30 years and most common symptom being progressive pallor. Anisocytosis, reticulocytosis, hypercellular marrow, and no marrow fibrosis were the most common hematological pictures. Severe pancytopenia was seen in aplastic anemia and acute leukemia.
Conclusion: The present study concludes that detailed clinical history and complete hematological investigations including bone marrow studies in patients presenting with symptoms of pancytopenia are essential in understanding the disease process and to delineate the causes of pancytopenia. We found aplastic anemia to be the most common etiology in our study, consistent with the studies of Kumar et al. and Niazi et al.
The following core competencies are addressed in this article: Practice-based learning and improvement, Patient care and procedural skills, Medical knowledge, and Professionalism

Keywords: Aplastic anemia, bone marrow, complete hemogram, etiology, pancytopenia


How to cite this article:
Mangal S, Sinha SS. Complete clinicopathological profile and etiological spectrum of pancytopenia in adult patients attending a tertiary care referral center in Eastern India. Int J Acad Med 2020;6:309-15

How to cite this URL:
Mangal S, Sinha SS. Complete clinicopathological profile and etiological spectrum of pancytopenia in adult patients attending a tertiary care referral center in Eastern India. Int J Acad Med [serial online] 2020 [cited 2021 Apr 12];6:309-15. Available from: https://www.ijam-web.org/text.asp?2020/6/4/309/304601




  Introduction Top


By definition, pancytopenia is a condition characterized by simultaneous presence of anemia, leukopenia, and thrombocytopenia.[1] It is not a disease entity, but a triad of findings that may result through different mechanisms such as destruction of marrow tissue by toxins, radiation (aplastic or hypoplastic marrow), replacement by abnormal or malignant tissue such as acute leukaemia, multiple myeloma, myelofibrosis, Hodgkin's and non-Hodgkin's lymphoma or suppression of normal marrow growth, and differentiation like megaloblastic anemia and systemic lupus erythematosus.[1],[2],[3]

It has been observed in the Indian scenario that megaloblastosis – Vitamin B 12 and folate deficiency - is the most common cause of pancytopenia.[4],[5],[6] Other important conditions manifesting as pancytopenia as reported include acute leukaemia, aplastic/hypoplastic anemia, paroxysmal nocturnal haemoglobinuria, overwhelming infections, and hypersplenism.[1] However, the frequency with which each condition is associated with pancytopenia differs considerably depending upon the various factors including geographical distribution and age.[6]

A look at both, Western and Indian literature shows that there are few comprehensive studies on pancytopenia. Thus, this study was undertaken to provide a complete profiling of pancytopenia which can guide future diagnostic workup and management of pancytopenia.


  Methodology Top


  • Study design/experiment design: Observational descriptive type of study with prospective design
  • Period of study: 24 months (2 years)
  • Study population: Patients attending the hematology outpatient department (OPD) of a tertiary care referral center in Kolkata who are diagnosed with pancytopenia
  • Sample size: 91 patients
  • Sample design: Purposive sampling
  • Control: Not required.


Inclusion criteria

Age >20 years, simultaneous presence of anemia: hemoglobin <13.5 g/dL (male) or 12 g/dL (female), leukopenia: total white cell count <4.0 × 109/L and thrombocytopenia: platelet count <150 × 109/L. We only included patients with the initial presentation of pancytopenia and not follow-up cases of already diagnosed pancytopenia.

Exclusion criteria

Patients on cancer chemotherapy, patients on other cytotoxic/antimetabolic drugs, patients on radiotherapy, patients who received recent blood transfusions, and patients with age ≤20 years were excluded from the study.

Study variables

Complete relevant medical history including age, sex, occupation, history of any treatment, intake or exposure to potentially toxic chemicals/agents/drugs, radiation exposure, history of symptoms such as fever, night sweats, malaise, weight loss, and pruritus were noted. Physical examination was done to check for pallor, jaundice, hepatosplenomegaly, lymphadenopathy, sternal tenderness, and gum hypertrophy. Evidence of hypersplenism and primary malignancy were searched for whenever necessary. Hematological investigations included complete blood count including peripheral smear examination, reticulocyte count, bone marrow aspiration, and bone marrow trephine biopsy.

Other investigations performed on case basis include liver function tests, vitamin B12/folate levels, coagulation profile, bone marrow cytogenetics, and blood/bone marrow immuno-phenotyping

Data collection and interpretation

Pretested, predesigned structured questionnaire with interview method.

The study was powered to be able to consent a certain number of patients to reach statistical significance on the parameters used. Synopsis was submitted to the Ethics Committee of Medical College, Kolkata, and after getting approval, the standard work plan was undertaken. Written consent from the patients or their parties was taken, and pretested interview schedule was filled up for collection of baseline information of the patients followed by their subsequent detailed laboratory work up. Interpretation of data was done by suitable charts and diagrams and appropriate statistical analysis for inference.


  Results Top


Out of 91 patients, majority of the study population (56%) were males, and male-to-female ratio was 1.27 [Table 1].
Table 1: Sex distribution of the patients

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Majority (24%) of the patients were young adults (age range 21–30) followed by patients in the age range 51–60 years (22%), and we found only 4% of patients were more than 70 years of age [Table 2].
Table 2: Age distribution of the patients

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The most common symptom was easy fatigability (68%) followed by bleeding manifestations (53%), fever, and weight loss. This indicates majority of the patients had the symptoms suggestive of anemia [Table 3].
Table 3: Distribution of symptoms among the patients

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Pallor was present in majority of the patients (80%), followed by splenomegaly (37%), lymphadenopathy, hepatomegaly, icterus, petechiae/purpura, and sternal tenderness [Table 4].
Table 4: Physical findings among the patients

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Hemoglobin level ranged from 2.9 g/dl to 10.8 g/dl. Majority of the patients had mild anemia (61%), followed by moderate (32%) and severe (7%) anemia [Table 5].
Table 5: Hemoglobin level among the patients

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Majority of the patients had normal mean corpuscular volume (MCV) (67%), followed by 23% of patients having macrocytic red cells (defined as MCV >100 fl) and only 10% having microcytic red cells (defined as MCV <80 fl) [Table 6].
Table 6: Distribution of mean corpuscular volume among the patients

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Total white blood cell count ranged from 300 to 4000/cc. Majority of the patients (56%) had moderate degree of leukopenia followed by 35% of patients with mild leukopenia and only 9% with severe leukopenia [Table 7].
Table 7: Distribution of total white blood cell count among the patients

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Absolute neutrophil count ranged from 0 to 3400/cc. Majority (36%) had ANC <500/cc followed by an equal percentage of patients (22%) for the range 501–1000/cc and more than 1000/cc [Table 8].
Table 8: Distribution of absolute neutrophil count among the patients

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Platelet count ranged from 2000 to 145000/cc. Majority of the patients (53%) belonged to the platelet range ≤25,000/cc, meaning most of them suffered from severe thrombocytopenia, followed by 20% with mild thrombocytopenia [Table 9].
Table 9: Distribution of platelet count among the patients

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Corrected reticulocyte count ranged from 0.01% to 5%. Majority of the patients (51%) had normal reticulocyte count between 0.5% and 1.5%, followed by almost similar percentage for low and high counts [Table 10].
Table 10: Distribution of corrected reticulocyte count among the patients

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Majority of the patients (49%) had a hypercellular marrow, followed by 29% of hypocellular marrow. Three patients had dilute marrow, whereas two patients had dry tap [Table 11].
Table 11: Distribution of bone marrow cellularity among the patients

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Bone marrow fibrosis (MF) grading was done using reticulin stain on bone marrow biopsy sections. Majority of the patients (76%) had a grade MF 0 meaning normal bone marrow or no fibrosis [Table 12].
Table 12: Distribution of bone marrow fibrosis among the patients

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Karyotyping was done by the cytogenetic analysis of bone marrow aspirate samples. Overwhelming majority (91%) had a normal karyotype. The most common karyotypic abnormality was del(11)(q23). Other abnormalities included del(20)(q12), 42~46, XY, 45~46, XX and 47, XY,+8 [Table 13].
Table 13: Distribution of karyotype among the patients

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In our study, the most common etiology was aplastic anemia (24.2%), followed by myelodysplastic syndrome (MDS) at 17.6% and acute leukemia (14.3%) [Table 14].
Table 14: Distribution of etiology among the patients

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In our study population, we encountered four subtypes of MDS. Using the 2016 classification of MDS, the most common subtype encountered was MDS with multi lineage dysplasia (59%) followed by MDS with single lineage dysplasia (23%) [Table 15].
Table 15: Distribution of subtypes of myelodysplastic syndrome among the patients

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  Discussion Top


In our study, the most common etiology was aplastic anemia (24.2%), followed by myelodysplastic syndrome (17.6%) and acute leukemia (14.3%). The most common cause for pancytopenia-aplastic anemia is consistent with studies of Kumar et al. and Niazi et al.[7],[8]

Total number of 91 cases with complete hematological work up including marrow examination were studied during our study period. The incidence of pancytopenia was 10%. Niazi andRaziq reported 19% incidence of pancytopenia.[8] The lower incidence in our study might be explained by the fact that we only included cases encountered in the OPD.

The age range in our study was 21–91 years. The maximum number, i.e., 59 cases (64.8%) occurred below the age of 50 years with majority, i.e., 22 cases (24%) occurring between 21 and 30 years. A slight male preponderance was seen. The overall male-to-female ratio was 1.27:1. Other studies also reported male preponderance. Khodke et al. studied 50 cases of pancytopenia and found maximum number of cases in the age group of 12–30 years (44%) with male-to-female ratio being 1.3:1.[4] Niazi et al. have also reported the most common age group between 21 and 30 years of age with male-to-female ratio being 1.7:1 in their study of 89 cases of pancytopenia.[8]

In our study, maximum number of cases of aplastic anemia (18%) was each in the age range 21–30, 41–50, and 51–60 years. Young et al. has reported peak incidences of ages 15–25 years and over 60 years in aplastic anemia.[9] Camitta et al. have reported a mean age of 50 years.[10] Tilak and Jain found 50% cases in the first and second decade and the remaining 50% in the sixth and seventh decade of life.[6] In our study, there were 16 cases of myelodysplasia, out of which there was male predominance and majority of the cases were in the 5th and 6th decade which was in line with the age group of MDS reported by Greenberg.[11] The age profiles of the acute leukemias differ, but overlap completely. Acute lymphoblastic leukemia (ALL) is predominant in young adults and acute myeloid leukemia (AML) in adults.[12] In our study, there were total 13 cases of acute leukemia, out of which two cases were of acute promyelocytic leukemia (APML). Four cases were in <40 years of age, and the remaining cases were in the fifth and sixth decades of life and all of them were AML. In our study, the maximum number of cases of megaloblastic anemia, i.e., eight out of total ten cases were below 50 years of age, with a peak in the second and third decades. Our findings are comparable with Sarode et al. and Kumar et al.[9],[13]

In the present study, progressive pallor (80.2%) was the most common clinical feature, and it was found in almost every case. Generalized weakness (68.1%), bleeding manifestations (52.7%), and fever (47.3%) were the other common presenting features. Bleeding manifestations were seen in 34% cases. Hepatomegaly was present in 24.2% cases, whereas splenomegaly was seen in 37.4% cases. Tilak and Jain, Khodke et al., Niazi and Raziq have reported that pallor was the predominant clinical feature and it was universally present in all the patients.[4],[6],[8] Khodke et al. have reported fever in 40% cases followed by weakness in 30% and bleeding manifestations in 20% of the cases. They have also reported splenomegaly in 40% and hepatomegaly in 38% of the cases in their study of 50 cases of pancytopenia.[4] Niazi et al. have reported weakness in 68.2% cases, fever in 47.7%, and bleeding in 33.7% cases of pancytopenia.[8]

In the present study, anisocytosis of varying severity was the most common morphologic type (58%) followed by normocytic normochromic (34%) and dimorphic anemia (8%). Hypersegmented polymorphs were in 14% cases, circulating immature cells in 25% cases, relative lymphocytosis in 24%, and reticulocytosis in 25.3% cases. Tilak and Jain have also reported the most common morphologic type as anisocytosis in 64% cases of pancytopenia. They have also reported hypersegmented polymorphs in 45% cases, circulating immature cells in 1.29% cases, relative lymphocytosis in 14.28%, and reticulocytosis in 7.79% cases in their study of 77 cases of pancytopenia.[6] Khodke et al. have also reported anisocytosis in 60% cases of pancytopenia representing the most common morphologic type. They have reported hypersegmented neutrophils in 40% cases, circulating immature cells in 4% cases, relative lymphocytosis in 10% cases, and reticulocytosis in 6% cases, in their study of 50 cases of pancytopenia.[4]

In the present study, 6 cases (6.6%) had hemoglobin levels ≤4 g/dl, suggesting severe degree of anemia at the time of presentation. Fity-one cases (56%) had total leukocyte count ranging from 1000 to 3000/mm3. Only eight cases (8.8%) had it below 1000/mm3. Eighteen cases (19.8%) had platelet counts between 50,000 and 1 lakh/mm3 but as many as 48 cases (52.7%) had platelet counts below 25,000/mm3.

In our study, we had a majority of cases (67%) with MCV within normal range, followed by 23% cases having macrocytic red cells with MCV >100 fl. The raised MCV was noted mainly in patients with MDS, Vitamin B12 deficiency, and chronic liver disease. We noted that around half of our cases had a normal reticulocyte count. While reticulocytosis was mostly noted in cases of acute leukemia, reticulocytopenia was present in the aplastic anemia group.[2],[3]

Bone marrow examination of 49% of the patients was hypercellular, 27% had hypocellular while 16.5% had normocellular marrow. This is consistent with the study by Gayathri et al. where hypercellularity was the most frequent bone marrow finding.[14] Bone marrow biopsy demonstrated majority of cases (76%) with no MF, while the most severe cases of MF were noted in primary myelofibrosis, hairy cell leukemia and aplastic anemia. This is comparable to the findings of Khodke et al.[4]

Cytogenetic analysis demonstrated a majority of cases (91%) had a normal karyotype. However Safaei et al. in their cytogenetic analysis of 100 patients showed 31% had an abnormal karyotype.[15] The commonest chromosomal abnormality noted was del (11)(q23) and we found it in cases with acute leukemia, MDS, aplastic anemia as well as SLE.

In our study, out of 91 cases, 22 cases (24.2%) were of hypoplastic/aplastic anemia group. International agranulocytosis and aplastic anemia study group, Imbert et al., Keisu et al. reported the incidence of aplastic anemia varying from 10% to 52.7% of all pancytopenic patients.[16],[17],[18] Thus, the commonest cause of pancytopenia reported from various parts of world has been aplastic anemia. This is comparable with the results of the present study. However different were the observations of Tilak and Jain who reported 68% cases of megaloblastic anemia in contrast to 7.7% cases of aplastic anemia in a study of 77 pancytopenia cases.[6] Also Khodke et al. reported 44% cases of megaloblastic anemia against 14% cases of aplastic anemia in a study of 50 cases of pancytopenia.[4] Probably this is due to our different study population which was only adult patients (>20 years age) as opposed to other studies.

Out of our total cases of pancytopenia, sixteen patients (17.6%) were of myelodysplasia. All showed dysplastic changes in erythroid and myeloid lineages with mild increase in iron. However, no ring sideroblasts were found. We applied WHO 2016 criteria and labelled these cases into the various subtypes. MDS multilineage dysplasia was the commonest subgroup (58.8%) followed by MDS single lineage dysplasia (23%). Kumar et al. and Khodke et al. have reported 3.6% and 2% cases of MDS as a cause of pancytopenia in their respective studies.[4],[9]

Third commonest cause in the present study was acute leukemia which showed thirteen cases (14.3%). Out of these, two were of APML type. Kumar et al., Kale et al. and Niazi et al. have reported 12%, 14.5% and 13.6% cases of acute leukemia as a cause for pancytopenia, in 166, 70 and 89 cases studied respectively.[8],[9],[19]

In the present study, the fourth common cause of pancytopnenia was megaloblastic anemia involving ten cases (11%). Pancytopenia in megaloblastic anemia appears to be commoner from various series – 68%, 44%, 47%, 25%, 64% and 39% reported by Tilak and Jain, Sarode et al., Mikiibi et al., Kale et al., Ng et al. and Sen et al. respectively.[6],[13],[19],[20],[21],[22]

We had three cases of lymphoma in our study. Similarly Tilak and Jain and Kumar et al. have reported two and ten cases of lymphoma in their respective studies.[6],[9] Out of our three cases of lymphoma one was of non-Hodgkin lymphoma (NHL) showing marrow involvement while one Hodgkin's and the other NHL didn't involve the marrow. But all of these cases had pancytopenia and therefore were included in the present study group.

In our study, there was one case of pancytopenia due to myelofibrosis. Patient was 38 years old male and presented with weakness, dyspnoea and splenomegaly. Peripheral smear showed the characteristic tear drop red cells with nucleated red cells, polychromasia along with hypersegmented polymorphs and immature neutrophils. Aspiration was a dry tap. But bone marrow biopsy revealed increased reticulin fibrosis of grade 3. Tilak and Jain and Kumar et al. have reported one and two cases of myelofibrosis in their studies of pancytopenia respectively.[6],[9]

Thus we have tried to present a complete profiling of all patients presenting with pancytopenia in our centre and we hope that our study can help in guiding a diagnostic workup for patients with pancytopenia at this centre in the future or when meta-analyses are done on published data on characteristics and diagnoses of patients with pancytopenia.


  Conclusions Top


The most common causes for pancytopenia in our study was aplastic anemia, followed by myelodysplasia and acute leukemia. The commonest age group for presentation of pancytopenia in adults was between 21 and 30 years, the male to female ratio being 1.27:1. The maximum number of cases of aplastic anemia were in the fifth decade while that of MDS were in the fourth to fifth decade. Progressive pallor was the most common clinical feature and universally present in all the patients. Generalised weakness, fever and bleeding manifestations were the other common presenting features. Severe pancytopenia was seen in aplastic anemia and acute leukemia whereas it was mild to moderate in other causes of pancytopenia. Anisocytosis of varying severity was the commonest morphologic type followed by normocytic normochromic and dimorphic anemia. Reticulocytosis was seen in one fourth of the cases of pancytopenenia. Most of the cases had a hypercellular marrow on bone marrow aspirate, no MF on bone marrow biopsy and normal Karyotype on cytogenetic analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Research quality and ethics statement

The authors of this manuscript declare that this scientific work complies with reporting quality, formatting and reproducibility guidelines set forth by the EQUATOR Network. The authors also attest that this clinical investigation was determined to require Institutional Review Board/Ethics Committee review, and the corresponding protocol/approval number is MC/KOL/IEC/Non-spon/451/11-2016.



 
  References Top

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Khodke K, Marwah S, Buxi G, Yadav RB, Chaturvedi NK. Bone marrow examination in case of pancytopenia. J Indian Acad Clin Med 2001;2:55-9.  Back to cited text no. 4
    
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Khunger JM, Arulsevi S, Sharma U, Ranga S, Talib VH. Pancytopenia - A clinicohematological study of 200 cases. Indian J Pathol Microbiol 2002;45:375-9.  Back to cited text no. 5
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Niazi M, Raziq F. The incidence of underlying pathology in pancytopenia – An experience of 89 cases. JPMI 2004;18:76-79.  Back to cited text no. 8
    
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Greenberg PL. The smoldering myeloid leukemic states – Clinical and biologic features (review). Blood 1983;61:1035-44.  Back to cited text no. 11
    
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Safaei A, Shokripour M, Omidifar N. Bone marrow and karyotype findings of patients with pancytopenia in southern Iran. Iran J Med Sci 2014;39:333-40.  Back to cited text no. 15
    
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13], [Table 14], [Table 15]



 

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