Approach to pancytopenia with case based discussion and brief details regarding each condition. Causes of pancytopenia. Details of congenital causes of aplastic anemia.
2. • Pancytopenia is defined as decrease in all three hematologic
cell lines.
• The condition is not a disease in itself but a common pathway
caused by various etiologies .
3. It is characterized (for Adults) by
• Hemoglobin < 12 g/dL in women and
13 g/dL in men,
• Platelets < 150,000 / μL,
• Leukocytes < 4 x 103/ μL or (Absolute neutrophil count < 1.8x
103/μL.)
4. It is characterized (for children) by
• Hemoglobin < 10 g/dL
• Platelets < 100,000 / μL,
• Leukocytes < 4 x 103/ μL or (Absolute neutrophil
count < 1.5x 103/μL.)
5. Reticulocyte production index (RPI)=
Patient’s hematocrit X retic count %
Normal hematocrit reticulocyte mat. Time
RPI is a good indicator of adequacy of the bone marrow response.
If RPI >2 good bone marrow response
RPI < 2 inadequate compensatory bone marrow response
10. Epidemiology
• Depending upon the cause , the disease presents in a varied
age group.
• Several studies in India by Chandra et al , Gayathri et al etc
showed megaloblastic anemia as the most frequent cause
followed by aplastic anemia.
12. FANCONI ANEMIA
• Multigenic, autosomal recessive disorder
• Common hereditary marrow failure disease , associated
with chromosomal breaks.
13. • Mutations result in defects in hematopoietic stem cells, and
the cells are ineffective in DNA repair (chromosomal
breakage disorder).
• Premalignant disorder – the long-term risk of progression to
MDS and AML.
16. Hematologic findings
• Severe pancytopenia with relative lymphocytosis
• Anemia is normocytic normochromic.
• Mild to moderate anisocytosis and poikilocytosis
• Decreased reticulocyte count
• Bone marrow is hypocellular with increased fat and infiltration by
lymphocytes and plasma cells.
• Erythroblasts are seen in the same stage of maturation.
• HbF is increased and i antigen expression on the red cells.
• Chromosomal breakage is demonstrable with DEB (diepoxybutane) and
Mitomycin C.
17.
18. DYSKERATOSIS CONGENITA
• X-linked recessive/autosomal dominant/autosomal recessive
disorder.
• Mutations in DKC1 at Xq28, a gene that encodes for dyskerin.
• Mutations in band 3q26 in TERC, a part of telomerase
complex
• Children with dyskeratosis congenita and telomeropathies in
adults - mutations in genes of telomerase complex / shelterin
complex.
19. • Cell lines affected Myeloid mainly, but
Erythroid & Megakaryocytic also affected.
• Monocytopenia is common Blood finding
23. GATA2 DISORDERS
• Autosomal dominant disorders with marrow failure,
MDS or AML.
• Heterozygous mutation in the GATA2 genes
• Bone marrow is hypocellular with multilineage
dysplasia, especially of megakaryocytes.
• Increase reticulin fibrosis occurs in marrow.
• Increased susceptibility to non tuberculous mycobacteria
and viral infections
• Monocytopenia, B and NK cell lymphocytopenia are lab
findings.
25. Diamond-Blackfan syndrome
• It is due to an intrinsic or regulatory defect in the
committed erythroid stem cell.
• Renal disease – decreased erythropoietin
• Endocrine deficiencies – may lead to decreased
erythropoietin production. For example:
hypothyroidism leads to decreased demand for
oxygen from tissues; decreased androgens in males;
decreased pituitary function.
26. Case 1
• A 4 year/female presented with generalized weakness and
bleeding gums .
• History of repeated blood transfusions +
• O/E – café-au-lait spots+ , mild deformity of fingers +
• Ps- NORMOCYTIC NORMOCHROMIC ANEMIA WITH
LEUCOPENIA (NEUTROPENIA ) AND THROMBOCYTOPENIA
• Reticulocytopenia
33. Degree of Severity of Aplastic Anemia
Severe aplastic anemia
bone marrow with < 30% cellularity
and presence of ≥ 2 of the following:
• Absolute neutrophil count < 500/uL (< 0.5 × 10^9/L)
• Transfusion dependance with ,ARC < 60,000/uL (< 60 ×
10^9/L)
• Platelet count < 20,000/uL (< 20 × 10^9/L)
Very severe aplastic anemia
Which fulfill the criteria of severe AA with an absolute
neutrophil count < 200/uL (< 0.2 x10^9/L).
34. Case 2
• 67 year/male previously well
• CBC normal last year
• presented with lethargy and gum bleeding since three weeks
• Hemoglobin 6,
• TLC 3000
• platelet 17000
• Examination
• well built ,pale looking ,no fever
• no significant drug history, no lymph node palpable
• no organomegaly
• iron ,vitamin b12, folate – all within normal range
• viral screening- all negative
35. • Peripheral blood film -Pancytopenia
• ARC reduced
• Bone marrow - hypocellular marrow
NORMAL BONE MARROW HYPOPLASTIC BONE MARROW
36. Hypocellular bone marrow ≠ aplastic anaemia
• Hypocellular MDS/AML /T LGL/ partiality treated ALL
• Viral infections parvovirus b19 ,hepatitis ,HIV
• Drug induced bone marrow - antineoplastic agents
,sulphonamides
• Auto immune diseases -SLE/RA
• Aplastic crisis in hemolytic anaemia transfusion associated
GVHD
• Inherited bone marrow failure syndrome eg.Fanconi anemia
37. Case 3
• 45 year/ male comes with a history of generalized weakness ,tingling
sensation
• numbness of hands and feet since 35 days with tinge of yellowish discoloration
• loss of appetite and significant weight loss with history of loose motions since
30 days
• hemoglobin 8g/dl
• TLC 1900 /cumm
• Neutrophil 74
• lymphocyte 29
• Eosinophils 4
• monocyte 3
• platelets 63000
• MCV 119fl
• MCH 28pg RDW 26.2
41. MEGALOBLASTIC ANEMIA
• Megaloblastic anemias are a group of disorders in which
the rate of DNA synthesis is retarded
• RNA synthesis is impaired to a lesser extent, resulting in
imbalanced cell growth.
• Cell populations undergoing rapid proliferation like the
hematopoietic cells manifest the alterations in cell size and
maturation.
42. • Symptoms of lethargy, Weakness, Glossitis, and
Neurological disturbances occur in cobalamin
deficiency.
43. • Bone marrow is markedly hypercellular with erythroid
hyperplasia
• The hallmark in the marrow is the nuclear-cytoplasmic
maturation dissociation, which is best seen in the erythroid
precursors .
• Megaloblasts have open sieve like nuclear chromatin
44.
45. Case 4
39 year old lady with history of generalized weakness , fever since
15 days
• bleeding from gums and nose ,ecchymotic patches since 3 days
• hemoglobin 7.3 g%
• total leukocyte count 1100 /cumm
• neutrophils 00 %
• lymphocyte 30%
• blasts 2%
• promyelocytes 68 %
• platelets 40000
• PT 64 seconds (control 12 sec )
• aPTT 98 seconds (control 30 sec)
46. • Fibrinogen 40 mg/dl
• Bleeding is out of proportion to thrombocytopenia
• Circulating promyelocytes without any mature neutrophils
50. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
• Life-threatening disorder, presented as pancytopenia.
• It can be either familial or sporadic, caused by various triggers
like infections, malignancies, rheumatologic and
immunodeficiency syndromes.
• It represents a severe hyperinflammatory condition with the cardinal
symptoms of prolonged fever ,cytopenia's ,
hepatosplenomegaly and hemophagocytosis by activated
macrophages.
51. • Initial evaluation should include complete blood count with
differential, coagulation studies, fibrinogen, serum ferritin
(usually>1000 mg/mL), liver function tests and triglycerides.
• Biopsies often reveal red cell ingestion by histiocytes
(hemophagocytosis)
• Treatment is corticosteroids, cyclosporin A, immunoglobulins ,
Etoposide.
52. Case 6
• 70 year old male with history of symptomatic anemia requiring
repeated blood transfusions since 3 months , pallor + , otherwise
unremarkable
• hemoglobin 5
• TLC 2700
• neutrophils 60
• lymphocytes 36
• Eosinophils 1
• monocytes 3
• Platelets 89000 MCV 127 fl MCH 28 pg, RDW 21.4
• retic count 1.5%
• bone marrow shows hypercellular bone marrow with trilineage
dysplasia with blasts
54. Myelodysplastic syndrome
• Myelodysplastic syndrome is a clonal stem cell disorder
characterized by dysplastic bone marrow.
• It usually affects elderly with a male predominance
• Peripheral blood findings are pancytopenia, bicytopenia, or
isolated cytopenias with reticulocytopenia.
• A macrocytic anemia is common, hypogranulated
neutrophils also seen in the smear.
• Morphologic evidence of dysplasia in the peripheral smear.
55. • Bone marrow aspirate shows normocellular or
hypercellular with various degrees of qualitative
abnormalities of one or more cell lineages.
• Flow cytometry and immunophenotyping helps in
differentiating MDS from other cytopenias in post cancer
therapy patients.
56.
57.
58. Case 7
• 75 year/male chronic alcoholic, fever, septic looking, acute
kidney injury ,pancytopenia
• hemoglobin 9 ,TLC 4 ,platelet 20000
• blood cultures taken
• started antibiotics
59. • peripheral blood smear -Anaemia ,thrombocytopenia ,shift to
lift ,leukoerythroblastic picture
• Neutrophils with toxic granulations and vaculations presence
of inclusion bodies ? bacilli within
neutrophil cytoplasm
• blood culture - listeria monocytogenes
65. Case 9
• 45 year / female presented with fatigue, abdominal
discomfort ,massive splenomegaly
• Pancytopenic picture
66. • Myelofibrosis
• no clinically relevant mutations were detected in JAK2, CALR
and MPL genes on this patient
• serum SSA /RO antibodies = 81.07 ( < 20)
67. Other causes of Myelofibrosis
• Primary autoimmune Myelofibrosis
• disseminated tuberculosis or histoplasmosis
• metastatic carcinoma (esp breast, prostate etc)
• other Myeloproliferative neoplasm in fibrotic phase
• Hairy cell leukemia
• renal osteodystrophy
• SLE/ scleroderma
• radiation exposure
• osteoporosis
• mastocytosis
68. PRIMARY MYELOFIBROSIS
• Primary myelofibrosis is one of the chronic
myeloproliferative neoplasms (MPN)
• Characterized by clonal proliferation of abnormal
megakaryocytes.
• Usually present with pancytopenia, extreme fatigue and an
enlarged spleen and liver .
• The peripheral smear shows leukoerythroblastic reaction
(myelophthisic smear), tear drop cells, left-shifted
(immature) white blood cells and nucleated RBCs
69. • Circulating CD34+ cells can help in distinguishing
this entity from other forms of myeloproliferative
disorders.
• Bone marrow aspiration usually is difficult, yielding
a dry tap, and bone marrow biopsy is necessary for
demonstrating reticulin fibrosis.
70. Case 10
• 55 year/ male alcoholic , anxiety disorder, no comorbidities
• fatigue since 3 months
• hemoglobin 8
• TLC 6500
• platelets 130000
• PS -marocytic RBCs
• LDH , b12 - normal
• bone marrow shows dysplasia in all three lineages
71. • Diagnosed as MDS
• tranfused 3 PRBCs , as routine- given B12 and folic acid
• asked to follow up with cytogenetics and biopsy report
72. • 15 days later
• appetite greatly improved
• general condition improved
• hemoglobin 10
• TLC 8500
• platelets 180000
73. Dysplastic changes in bone marrow
• megaloblastic anaemia
• heavy metal toxicity
• alcohol abuse
• HIV , parvovirus
• anti-tubercular therapy
• drugs- chemotherapy , valproate
• chronic liver disease
• if all the above our ruled out- myelodysplastic syndrome
74. Case 11
• 45 year /male
• in ICU ,alcoholic
• pneumonia with sepsis
• pancytopenia -worsening rapidly
75. • Bone marrow aspiration- dilute
• Bone marrow biopsy shows necrosis
78. Storage disorders
• Gaucher disease - inherited lysosomal storage disease -
autosomal recessive defect of the gene encoding β-
glucocerebrosidase,
• The lipid-laden cells are called Gaucher cells and are
predominantly found in the spleen, liver, bone marrow
and rarely lung.
• Clinical presentation- hepatosplenomegaly, pancytopenia,
bone complications
79.
80. HYPERSPLENISM
• Hypersplenism is characterized by anemia , leukopenia
and/or thrombocytopenia.
• It causes pancytopenia by splenic sequestration
• Causes - Cirrhosis, congestive heart failure, malignancies
like leukemia/lymphoma and infections like TB, typhoid
fever , malaria , leishmaniasis etc
• Patients can present with pain or fullness in the left upper
quadrant, abdominal distension or referred pain to the
shoulder.
81. Paroxysmal nocturnal
hemoglobinuria
• PNH is an acquired mutation in the PIGA gene ( X chromosome)
resulting in defective cell membrane leading to hemolysis,
pancytopenia and thrombosis.
• Defect in glycosylphosphatidylinositol (GPI linked proteins ) – CD 55
and CD 59 (membrane associated complement regulatory proteins.)
82. • Anemia symptoms – jaundice , morning cola colored urine
Hematologic findings-normocytic normochromic, increased reticulocyte
count.
• Cases with marrow failure, display leucopenia, thrombocytopenia and low
reticulocyte counts.
83. • Bone marrow- cellular, erythroid hyperplasia. In later stages aplasia
supervenes and may be difficult to differentiate fromAplastic Anemia.
• Iron stores are usually nil in PNH, while they are increased in AA.
• Diagnosis- Flow cytometry detects CD16/CD66b in granulocytes &
CD55,CD59 in RBCs.
• Flow cytometric analysis (FLAER) of granulocytes and red cells for CD56
and CD59 is useful in distinguishing AA from PNH overlap syndrome.
84. • Large granular Lymphocyte (LGL) leukemia is a clonal disorder
affecting the large granular lymphocytes which can cause marrow
infiltration leading to cytopenia.
• The diagnosis is based on immunophenotypic analysis of the
peripheral smear but bone marrow biopsy/aspirate may be
required in some cases
• HCL typically presents with massive splenomegaly and
pancytopenia.
• Granulomatous diseases like miliary TB and sarcoidosis and
metabolic disorders like Gaucher disease can also cause
pancytopenia by causing intense marrow infiltration.
85. Pancytopenia may present with the following emergencies
• Febrile Neutropenia
• Metabolic emergencies (e.g., symptomatic hyperkalemia,
hypercalcemia, tumor lysis syndrome)
• Disseminated intravascular coagulation
• Hemophagocytic lymphohistiocytosis
• Abnormal peripheral blood smear (e.g., microangiopathy, blasts)
• Severe aplastic anemia
• Symptomatic anemia (e.g., cardiac ischemia, hemodynamic
instability, worsening congestive heart failure)
• Thrombocytopenia (platelets <10,000/microL, or <50,000/microL
associated with bleeding)
86. when to say pancytopenia urgent?
• Absolute neutrophil count <1000/ ul with fever or other
evidence of infection
• or <500/ul
• symptomatic anemia
• thrombocytopenia
• platelets < 10,000 /uL or platelets < 50,000 / uL with clinical
significant bleeding
When is a referral less urgent?
• Asymptomatic
• Blood counts stable
88. History Taking
• Severity and durations of symptoms
• Constitutional symptoms - fever , night sweats , weight loss , fatigue
• Age
• Mucosal Bleeding
• Jaundice
• Joint pain
• Diet history
• Infections
• Previous treatment history
• Drug history
• Alcohol consumption history
• Family history
90. – CBC with Peripheral smear and Reticulocyte count
– Vitamin B12 and folate assays
– LFT
– Serum iron profile
– Serology – HIV, HBsAg and HCV
91. What to look in the Peripheral Blood Smear?
• Red Cells – Macrocytes, Ovalocytes, Tear drop forms,
Nucleated RBCs
– Inclusions – Cabot rings, basophilic stippling, siderocytes
• WBC – Hypersegmented neutrophils, Hyposegmented-
hypogranular neutrophils, hairy cells, Large granular
lymphocytes, Abnormal promyelocytes, Blasts, Shift to left
• Platelets – Giant or small sized
• Hemoparasites
92.
93. • Further Work-up
• Bone marrow Morphology
• Serological testing for viruses, auto-immune disorders
• Cultures
– Ancillary testing
• Flow cytometry / Immunophenotyping
94. Bone Marrow Evaluation
• Not required – if Vitamin B12 or folate
assays are low, consistent with
Megaloblastosis
• Yes for all Pancytopenias
– When levels of Vitamin B12 and / or folate assays
cannot explain the degree of severity of
Pancytopenia
98. Summary
• Pancytopenia is a decrease in all three blood cell lines with a
wide list of possible causes.
• Most common causes include megaloblastic anemia, aplastic
anemia myelodysplastic syndrome and acute leukemia
• Hypersplenism ,infections and drugs .
• Urgency of evaluation depends primarily on the severity and
duration of symptoms.
• Management focuses primarily on stabilizing clinical status
followed by thorough investigation to identify the cause.
99. Reference
• Singh T. Atlas and Text of Hematology: 4th edition. New Delhi: Avichal
Publication Company; 2018
• Mckenzie SB, Williams JL. Clinical Laboratory Hematology: 4th edition.
Boston: Pearson; 2016
• Greer PJ et al. Wintrobe’s Clinical Hematology: 14th edition. Philadelphia:
Wolters Kluwer; 2019
• Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease.
10th ed. Vol I. New York: Elsevier; 2021.
• Chandra, Harish, Gupta, Arvind K,Nath, Uttam K, Singh, Neha; Kumar, Utpal,
Kishore, Sanjeev.Clinico-hematological study of pancytopenia: A single-center
experience from north Himalayan region of India. Journal of Family Medicine
and Primary Care 8(12):3944-3948;Dec2019.
• Gayathri BN, Rao KS. Pancytopenia: a clinico hematological study. J Lab
Physicians;3(1):15-20;Jan 2011
• Chiravuri S, De Jesus O. Pancytopenia. [Updated 2023 Aug 23]. In: StatPearls
[Internet].Treasure Island (FL): StatPearls Publishing;Jan 2023
• Sharma A,Rajeshwari K, Kumar D,Clinicoetiological profile of children with
bicytopenia and pancytopenia,Pediatric Hematology Oncology Journal,8 (1).
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