Pathology

Clinico-Haematological Study Of Pancytopenia- An Experience From Tertiary Care Hospital

Global Journal of Pathology & Laboratory Medicine
Volume 1, Issue 4, January 2022, Pages: 64-74
Received: January 7th, 2022, Reviewed: January 10, 2022, Accepted: January 20, 2022, Published: January 28, 2022

Unified Citation Journals, Pathology 2022, 1(4) 1-10; https://doi.org/10.52402/Pathology210
ISSN 2754-0952

Authors: Dr. Chanda Varshini Sindhiya 1, Dr. Suresh Hanagavadi 2

1 Department of Pathology, Postgraduate, JJM Medical College, RGUHS, Davangere, Karnataka, India
2 Department of Pathology, Professor, JJM Medical College, Davangere, Karnataka, India

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Keywords: Anemia, Pancytopenia, Aspiration, Marrow

1. Abstract:
Pancytopenia is a condition in which red blood cells, white blood cells, and platelets are lower than the normal range. It occurs when there is a problem with blood-forming stem cells in the bone marrow. The approach in diagnosis includes good history, clinical examination, complete haemogram, and bone marrow examination for appropriate management. The present study was done to understand various aetiological factors for pancytopenia by correlating clinical and haematological investigations along with bone marrow examination. It was 3 years retrospective study from December 2018 to December 2021 done in the Haematology Unit, Department of Pathology, JJM Medical College, Davangere. 100 patients referred from clinical departments with indications for Bone marrow examination were included in the study. Special stains were done wherever required. The age ranged from 45days to 85years had male preponderance with generalized weakness, easy fatiguability, and fever being common complaints. The common examination finding was pallor and splenomegaly. Others include hepatomegaly, lymphadenopathy, icterus, oedema, knuckle pigmentation, and bald tongue. Complete haemogram and bone marrow aspiration was done in all cases. The commonest cause of pancytopenia was Megaloblastic anemia accounting for 37%, followed by Combined nutritional deficiency 24%, Aplastic anemia 12%, Iron deficiency anemia 9%, Normal 8%, APL 2%. ALL L1, ALL L2, NHL, JMML, MDS, PMF, and Storage disorder of 1% each and Inconclusive only 1%. The present study concludes that detailed clinical and haematological investigations with bone marrow examination determine the accurate diagnosis of the cause for pancytopenia and properly management

2. Introduction
Pancytopenia is a combination of anemia, leucopenia, and thrombocytopenia with hemoglobin < 9g/dl, total leucocyte count < 4 x 109/L, and platelet count <140 x 109/L. Neutropenia (Absolute neutrophil count < 1.5 x 109/L) is more important than leucopenia.
It occurs when there is a problem with blood-forming stem cells in the bone marrow [12].
It is the manifestation of many serious and life-threatening diseases. For establishing proper diagnosis detailed history, clinical examination, complete haemogram, and bone marrow examination is needed for appropriate management.
Peripheral smear plays a major role in revealing important information regarding aetiology e.g., macro-ovalocytes with hypersegmented neutrophils in megaloblastic anemia, occasional blast cells in subleukemic leukemia, leucoerythroblastic blood picture in myelofibrosis and Pelger-Huet neutrophils in myelodysplastic syndrome. In some cases like aplastic anemia, acute leukemias, myelofibrosis imprint/touch smears are more useful than marrow aspirate as they yield dry or bloody tap on aspirate[12].
The main aim and objective of the study were to know the clinico-haematological profile of patients presenting with pancytopenia and to understand various aetiological factors causing pancytopenia.

2. Material and Methods
2.1 Source of data
A retrospective study was done from December 2018 to December 2021 of about 100 cases on clinically diagnosed cases of pancytopenia who came for bone marrow examination to Haematology Unit, Department of Pathology, JJMMC, Davangere, RGUHS, Karnataka, India.

2.2 Method of collection of data
2.2.1 Data archive
Patients referred from clinical departments having pancytopenia with an indication for Bone marrow examination were included in the study while patients with inherited bleeding disorders are excluded.
Demographic data, detailed history, clinical examinations, and haematological parameters at presentation were recorded. Haematological parameters included hemoglobin, red blood cell, Packed Cell Volume, total leucocyte count, Mean Corpuscular Volume(MCV), Mean Corpuscular Hemoglobin(MCH), Mean Corpuscular Hemoglobin Concentration (MCHC), Platelet and Reticulocyte count. Bone marrow aspiration was carried out in all the cases, biopsy and imprint were done wherever possible and special stains were performed if necessary. Requisition forms and registers containing information regarding patients and slides are taken from departmental archives. Ethical Committee clearance had been obtained from our institution for this study.

2.2.2 Statistical analysis
It is descriptive statistics using percentages, mean, and range.

3. Results
100 cases fulfilling inclusion criteria and with a definite diagnosis were studied for aetiology of pancytopenia. The age group ranged from 45 days old to 85 years with a mean age of 42 years. The most commonly affected age group was 0-25 years accounting for (46%), 25-50 (35%), 50-75 (15%), and 75-100 being less of about (4%) (Figure 1). M: F ratio was 1.25:1 with male preponderance.
Generalized weakness was the most common clinical presentation seen in 60(60%) cases out of 100, followed by easy fatiguability in 45(45%), fever in 36 (36%), pain in the abdomen in 14(14%). Loss of appetite, headache, giddiness in 10 (10%). Breathlessness in 8(8%). Cough and loss of weight are the least common complaints seen in 4 (4%) and 2 cases(2%) respectively. Vomitings, loose stools, and failure to thrive are seen in 1 case each(1% each) (Table 1).
On clinical examination, pallor was seen in all 100 cases (100%), followed by splenomegaly 41 (41%), hepatomegaly 16 (16%), lymphadenopathy 10 (10%), icterus 4 (4%), oedema and knuckle pigmentation each 3(3%), bald tongue 1(1%). Cyanosis and clubbing are not seen in any of these cases (0%) (Table 2).

Figure 1 Age distribution

Figure 1: Age distribution
Chief complaints
 

  n=100

     (%)

 

Generalised weakness 60 60%
Easy fatiguability 45 45%
Fever 36 36%
Pain in abdomen 14 14%
Loss of appetite 10 10%
Headache 10 10%
Giddiness 10 10%
Breathlessness 8 8%
Cough 4 4%
Loss of weight 2 2%
Vomitings 1 1%
Loose stools 1 1%
Failure to thrive 1 1%

Table 1: Clinical presentation findings

Following haematological parameters were noted with Hb ranging from 2.3 to 11.7g/dl with a mean of 7g/dl, RBC 0.7 to 3.7 million/cumm with a mean of 2.2 million/cumm, PCV 6.4% to 41.3% with a mean of 23.85%, WBC 600 to 3920 cells/cumm with mean of 2260cells/cumm, MCV 62.2 to 132.3fL with a mean of 97.25fL , MCH 16.0 to 45.1pg with a mean of 30.55pg, MCHC 23.2 to 47.9g/dl with a mean of 35.55g/dl, platelet count 0.02 to 1.34 lakhs/cumm with mean of 0.68 lakhs/cumm and retic count 0.02 to 2.5% with mean of 1.01% (Table 3).
Megaloblastic anemia was most common accounting for 37(37%) cases out of 100, followed by Combined nutritional deficiency 24(24%), Aplastic anemia 12 (12%), Iron deficiency anemia 9 (9%), Normal 8(8%), APL 2 (2%). ALL L1, ALL L2, NHL, JMML, MDS, PMF, Storage disorder(? Gauchers) of 1 case each(1%each) and Inconclusive only in 1(1%) (Table 4).

Signs    
    n=100 (%)
Pallor 100 100%
Splenomegaly 41 41%
Hepatomegaly 16 16%
Lymphadenopathy 10 10%
Icterus 4 4%
Oedema 3 3%
Knuckle Pigmentation 3 3%
Bald tongue 1 1%
Clubbing 0 0%
Cyanosis 0 0%

Table 2: Clinical Examination findings

CBC      
   

 Minimum

           Maximum                       Mean
Hb 2.3g/dl

 

11.7g/dl

 

7g/dl

 

RBC 0.7million/cumm

 

3.7million/cumm

 

2.2million/cumm
PCV 6.4%

 

41.3%

 

23.85%

 

WBC 600

cells/cumm

 

3920

cells/cumm

 

2260

cells/cumm

 

MCV 62.2fL

 

132.3fL

 

97.25fL

 

MCH 16.0pg

 

45.1pg

 

30.55pg

 

MCHC 23.2g/dl

 

47.9g/dl

 

35.55g/dl
PLT 0.02lakhs/

cumm

 

1.34lakhs/

cumm

 

0.68lakhs/

cumm

Retic% 0.02%

 

2.5%

 

1.01%

Table 3: Variation of hematological parameters

Condition    
  n=100 (%)
Megaloblastic anemia 37 37%
Combined nutritional deficiency 24 24%
Aplastic anemia 12 12%
Iron deficiency anemia 9 9%
Normal 8 8%
Acute promyelocytic leukemia (APL)

(Acute myeloid leukemia (AML M3- FAB))

2 2%
Acute lymphoblastic leukemia (ALL L1) 1 1%
Acute lymphoblastic leukemia (ALL L2) 1 1%
Non hodgkin lymphoma (NHL) 1 1%
Juvenile myelomonocytic leukemia (JMML) 1 1%
Myelodysplastic syndrome(MDS) 1 1%
Storage disorder(?gauchers) 1 1%
Primary myelofibrosis(PMF) 1 1%
Inconclusive 1 1%

4. Discussion
The pattern of diseases leading to pancytopenia may vary in different population groups with their differences in age pattern, nutritional status, and the prevalence of infections. This study is done in all age groups. In our study, the age group ranged from 45 days old to 85 years with a mean age of 42 years. M: F ratio was 1.25:1 with male preponderance. The most common presenting complain was Generalised weakness, easy fatiguability, and fever. The most common examination findings were pallor and splenomegaly. Others are hepatomegaly, lymphadenopathy, icterus, oedema, knuckle pigmentation, and bald tongue.
Laboratory analysis included Hb, RBC, PCV, WBC, MCV, MCH, MCHC, differential count, platelet, and reticulocyte count was done using an automated blood analyzer. Bone marrow was done from the posterior superior iliac spine under aseptic precautions and consent was taken in all cases from the patient or guardian.
A bone marrow study was done to look for cellularity, morphology, type/abnormal maturation, infiltration-neoplastic/non-neoplastic, metastatic deposits. Morphological features of all conditions varied (Figure 2) (Figure 3). Special stains were done for a few (Figure 4).
Aetiopathogenesis of pancytopenia was different in different cases with variable haematological results(Table 5). Considering all results we have found that pancytopenia with normocytic normochromic blood picture with any atypical cells is key to suspect malignant conditions.
All 100 cases showed red blood cells, white blood cells and platelet count less than the normal range suggesting pancytopenia with an indication for bone marrow examination.
In this study megaloblastic anemia was the most common cause of pancytopenia accounting for (37%), followed by others Combined nutritional deficiency (24%), Aplastic anemia (12%), Iron deficiency anemia (9%), normal (8%), APL(2%). ALL L1, ALL L2, NHL, JMML, MDS, PMF, and Storage disorder of (1% each) and Inconclusive only (1%).

Figure 2: (A) - Megaloblasts in megaloblastic anemia (B)-Micronormoblastic erythropoiesis in iron deficiency anemia (C, D)- Both megaloblasts and micronormoblastic erythropoiesis in combined nutritional deficiency (E)-Sparsely cellular and filled with fat spaces in aplastic anemia (F)- Myeloblasts in APL(G)- Promyelocytes with Auers rods and faggot cells in APL
Figure 2: (A) – Megaloblasts in megaloblastic anemia (B)-Micronormoblastic erythropoiesis in iron deficiency anemia (C, D)- Both megaloblasts and micronormoblastic erythropoiesis in combined nutritional deficiency (E)-Sparsely cellular and filled with fat spaces in aplastic anemia (F)- Myeloblasts in APL(G)- Promyelocytes with Auers rods and faggot cells in APL
Figure 3: (H) Small cells in ALL L1 (I) Large cells with abundant basophilic cytoplasm in ALL L2 (J, K)- Heterogenous population of small and large cells in NHL (L)- Metamyelocytes, myeloblasts and promonocytes in JMML (M, N)- Pelger-Huet neutrophil and dyserythropoiesis in MDS (O,P,Q)- Leukoerythroblastic picture, Inter and intra trabecular fibrosis with no megakaryocyte, Dilated sinusoids with absent megakaryocyte within it – Overt stage PMF (R,S)- Gaucher cells with “wrinkled tissue paper appearance” in Gauchers disease
Figure 3: (H) Small cells in ALL L1 (I) Large cells with abundant basophilic cytoplasm in ALL L2 (J, K)- Heterogenous population of small and large cells in NHL (L)- Metamyelocytes, myeloblasts and promonocytes in JMML (M, N)- Pelger-Huet neutrophil and dyserythropoiesis in MDS (O,P,Q)- Leukoerythroblastic picture, Inter and intra trabecular fibrosis with no megakaryocyte, Dilated sinusoids with absent megakaryocyte within it – Overt stage PMF (R,S)- Gaucher cells with “wrinkled tissue paper appearance” in Gauchers disease
Figure 4: Pearls stain with depleted iron deposits suggestive of iron deficiency anemia
Figure 4: Pearls stain with depleted iron deposits suggestive of iron deficiency anemia
Condition and No. of cases (n=100) Age/ Sex Clinical presentation and examination findings Haematological parameters Bone marrow
Megaloblastic anemia (37 cases) Age range of  45days-85years

M:F (1.2:1)

Generalised weakness, fever and fatigue in few

Pallor, splenomegaly, hepatomegaly, knuckle pigmentation and bald tongue

MCV and MCH ( )

Peripheral smear showed pancytopenia with macrocytic blood picture

Megaloblastic erythroid hyperplasia with intermediate and late megaloblasts, cells with nuclei show open sieve like chromatin and royal blue cytoplasm
Combined nutritional deficiency (24 cases) Age range of

11-73years

M:F (1.2:1)

Generalised weakness, easy fatiguablity and fever in few

Pallor

MCV and MCH (Normal)

Peripheral smear of all cases demonstrated pancytopenia with dimorphic picture (microcytic hypochromic and macrocytes)

Cells with nuclei shows open sieve like chromatin and royal blue cytoplasm suggestive of megaloblasts with micronormoblasts

 

Aplastic anemia (12 cases) Age range of

6-60 years

F:M ratio (3:1)

 

Generalised weakness and few with easy fatigue

Pallor

MCV and MCH (Normal)

Peripheral smear demonstrated pancytopenia with normocytic normochromic and few macrocytic Rbc’s

 

Hypocellular showed predominantly fat spaces with sparse haemopoietic elements
Iron deficiency anemia (9 cases)

 

Age range of

21-76years

M:F (1.3:1)

 

Generalised weakness and few with easy fatigue

Pallor

MCV and MCH ( )

Peripheral smear demonstrated pancytopenia with microcytic hypochromic blood picture

 

Micronormoblastic erythroid hyperplasia

Pearls stain- depleted iron deposits

APL (2 cases) One case is 15/F and other was 16/M

M:F (1:1)

Severe headache and giddiness

Pallor and Splenomegaly

MCV and MCH (Normal)

Peripheral smear showed pancytopenia with normocytic normochromic Rbc’s , promyelocytes and myeloblasts

Myeloblasts, promyelocytes being hypergranular and faggots of auer rods seen
ALL L1 (1 case) 16/F

 

Generalised weakness

Pallor, Hepatosplenomegaly and generalized lymphadenopathy

 

MCV and MCH (Normal)

Peripheral smear showed pancytopenia with normocytic normochromic Rbc’s and increased lymphocyte count

Lymphoid cells composed of small cells. Small cells have scanty rim of blue cytoplasm, round nuclei with 0-1 nucleoli and coarse clump chromatin
ALL L2 (1 case) 8/M

 

Generalised weakness

Pallor, Hepatosplenomegaly and generalized lymphadenopathy

 

MCV and MCH (Normal)

Peripheral smear showed pancytopenia with normocytic normochromic Rbc’s and increased lymphocyte count

Large cell with ( ) N:C ratio, irregular nuclear membrane, clump chromatin, moderate amount of basophilic cytoplasm, few blasts shows vacuolation with 1-2 prominent nucleoli
NHL (1 case) 7/M Fever

Pallor, Bilateral cervical lymphadenopathy along with supraclavicular, axillary, inguinal lymphnode and mild hepatosplenomegaly

MCV and MCH (Normal)

Peripheral smear showed pancytopenia with normocytic normochromic Rbc’s and increased lymphocyte count

Small cells are with a scanty rim of cytoplasm and 0-1 nucleoli. Large cells show mild to moderate amount of basophilic cytoplasm, nucleus showed 1-2 nucleoli and cytoplasmic vacuolation
JMML (1 case) 9 months/M Fever

Pallor and hepatosplenomegaly

MCV and MCH (Normal)

Peripheral smear showed pancytopenia with normocytic normochromic Rbc’s, myelocytes, metamyelocytes and band forms. Occasionally seen circulating myeloblast

Hypercellular, Erythropoiesis ) normoblastic maturation, Myelopoiesis ( with predominance of myelocytes, metamyelocytes,band forms.myeloblasts and promonocytes
MDS (1 case) 80/M Generalised weakness and loss of appetite

Pallor

MCV and MCH ( )

Peripheral smear showed pancytopenia with macrocytic Rbc’s  with hypogranular neutrophils and ‘Pince-nez type’ neutrophil(Pelger-Huet neutrophils) and nuclear hyposegmentation

 

Dyserythropoiesis in >10% of cells suggesting dysplasia

 

Storage disorder(?Gauchers) (1 case)

 

6 months/F Vomitings, loose stools, failure to thrive

Pallor and ecchymosis

MCV and MCH (Normal)

Peripheral smear showed pancytopenia with normocytic normochromic Rbc’s

Clusters of gaucher cells with small eccentric nucleus  and abundant cytoplasm having characteristic “wrinkled tissue paper appearance”
PMF (1 case) 36/F Abdominal pain, breathlessness and fever

Pallor and Splenomegaly

MCV and MCH ( )

Peripheral smear demonstrated pancytopenia with macrocytic red blood cells with characteristic tear drop cells and few precursors like metamyelocytes and myelocytes favouring leukoerythroblastic picture

 

Aspiration– Intermediate and late normoblasts with some megaloblastic maturation and reduced myelopoiesis and megakaryopoiesis

Biopsy – Intra and inter trabecular areas are seen with marked fibrosis and osteosclerosis and dilated sinusoids with no megakaryocyte (overt stage PMF)

Imprint- fat spaces and sparsely cellular.

Reticulin stain – grade 3

Table 5: Aetiopathogenesis of pancytopenia with haematological features

According to the study by Ghartimagar D et al. age range from 2-82years with male preponderance, generalized weakness, and fever being the common presentations of patients. Common examination findings are pallor. The most common cause for pancytopenia among 130 cases was hypoplastic marrow (38), megaloblastic anemia (26), and acute leukemia (19)
100 case study done by Rangaswamy M et al. age range from 11-30years with male preponderance, generalized weakness and fatigue being a common presentation of patients. Megaloblastic anemia(33) was the most common cause noted.
Khunger JM et al. study found that out of 200, the most commonest cause of pancytopenia was megaloblastic anaemia (144), whereas Kumar et al 166 case study showed major causes as aplastic anemia(49) followed by megaloblastic anemia(37), aleukemic leukemia or lymphoma(30) and hypersplenism(19)
Tilak V et al. has done a bone marrow study on 77 cases revealed megaloblastic anemia(52) is the most common
202 case study done by Varma N et al. showed aplastic anemia (82) as the most common cause followed by megaloblastic anemia(48) and acute myeloblastic leukemia(26)

5. Conclusion
Megaloblastic anemia is the most common and major cause of pancytopenia, where patients come in the acute phase in the critically ill stage if diagnosed properly is rapidly correctable and disease is reversible. Thus, the comprehensive clinical and haematological study of patients with pancytopenia will usually help in the identification of the underlying cause. However, in view of a wide array of aetiologies, pancytopenia continues to be a diagnostic challenge for hematologists. Thus, correlation with bone marrow examination always helps in diagnosing appropriately for timely management and help patients improve drastically.

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To citation of this article: Dr. Chanda Varshini Sindhiya, Dr. Suresh Hanagavadi, Clinico-Haematological Study Of Pancytopenia- An Experience From Tertiary Care Hospital, Global Journal of Pathology & Laboratory Medicine

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