Approach to Pancytopenia

Dr. Murtaza KamalMBBS, MD, DNBClinical Fellow (Pediatric Hemato-Oncology)Rajiv Gandhi Cancer Institute & Research Center,Rohini, New DelhiDt: Feb 16,2017

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The terms…

• Cytopenia: Reduction in either of the cellular component of blood

• Bicytopenia: Reduction in any of the 2 two cell lines of blood• Anemia + Thrombocytopenia- 77.5%• Anemia + Leukopenia-17.3%• Thrombocytopenia + Leukopenia-5.5%*

• *Neelam Verma et.al. Pediatric patients with bicytopenia/pancytopenia: Review of etiologies and clinicao-hematological profile at a tertiary center. Indian Journal of Pathology and Microbiology;54(1), Jan-Mar 2011.

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The terms…(cont.)• Pancytopenia: Reduction in all 3 cell lines of blood The values of the 3 components being:• Hb <13.5(M)/ 11.5(F) g/dl• TLC< 4000/cu mm• Platelets <1,50,000/ cu mm*

• *De Gruchy GC. Pancytopenia, aplastic anemia. De Gruchey’s clinical hematology in medical practice. 5th edition• *Frank F. De Gruchey’s clinical hematology in medical practice. 5th edition. Blackwell:Berlin;2004:1199.

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It can occur due to:

• Bone marrow failure• Marrow space occupying lesions• Ineffective marrow production• Peripheral destruction of hematopoietic cells

• Elizabeth P. et al. The differential diagnosis and bone marrow evaluation of new onset Pancytopenia. AM J Clin Pathol 2013;139:9-29. 4

Causes…

CAUSES OF

PANCYTOPENIA

INHERITED

ACQUIRED 5

Inherited Causes…

Elizabeth P. et al. The differential diagnosis and bone marrow evaluation of new onset Pancytopenia. AM J Clin Pathol 2013;139:9-29.

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Causes of childhood pancytopenia

Category Condition B M Appearance

Aplastic anemia Idiopathic Hypocellular

Inherited BM failure syndromes

Hypocellular

Drugs/Toxin associated Hypocellular

Megaloblastic Anemia Acquired Hypercellular

Congenital deficiency Hypercellular

Malignant infiltration ALL/AML Hyper/Hypocellular

MDS Hyper/Hypocellular

Hodgkin’s disease Infiltrated

Solid tumors Infiltrated

Histiocytic Syndromes Hypocellular with hemophagocytosis

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Causes of childhood pancytopenia (Cont.)

Category Condition B M Appearance

Non-malignant infiltration Storage disorders Infiltrated

Osteopetrosis Increased bony trabeculae

Infection CMV, EBV, Parvovirus, HHV-6, Hepatitis, HIV

Hypocellular(Pro-erythroblasts in parvo-virus)

Immune disorders SLE Hypercellular

Evan’s syndrome Hypercellular

Thymoma Hypocellular9

Causes of childhood pancytopenia (Cont.)

Category Condition B M AppearanceAcquired clonal bone marrow failure disorder

PNH Variable

Metabolic Hypothermia Variable

Anorexia nervosa Hypocellular with fat necrosis

Others Hypersplenism Hypercellular

*Bharat R Agarwal et al. Aplastic Anemia: Current Issues in Diagnosis and Management. Practical Pediatric Hematology. 2nd edition. Jaypee pg 58

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Common causes in Indian Children*

Neelam Verma et al. Pediatric patients with bicytopenia/pancytopenia; Review of etiologies and clinico-hematological profile at a tertiary center.Indian Journal of Pathology and Microbiology. 54(1), Jan-March 2011. PGI-Chandigarh

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Common causes in our country(Cont…)*

Jain A et al. An etiological reappraisal of pancytopenia- Largest series reported to date from a single tertiary care teaching hospital. BMC Hematology,13,10. 2013. Maharastra

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How to approach?

History Physical Examination Investigations

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Points to consider in history• Age• Sex• Duration of symptoms• Bone pains, fever, night sweats, malaise, weight loss• Bleeding from any site• Jaundice• Joint pain, rash, photosensitivity• Any radiation exposure• Exposure to potentially toxic chemicals• Treatment history including herbals and drug intake, blood

transfusions• Dietary history• Occupational exposure history

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Clinical Examination• Anthropometry including stature • Dysmorphic features• Pallor, Jaundice, Lymphadenopathy, Edema• Sings of CHF• Stomatitis, cheilitis• Nail dystrophy, leukoplakia, skin pigmentation• Oral candidiatis, pharyngeal exudates• Petechie, purpura, hyperpigmentation• Sternal tenderness• Gum hypertrophy• Hepatosplenomegaly• Joint swelling, sinuvitis

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Signs & Symptoms

Neelam Verma et al. Pediatric patients with bicytopenia/pancytopenia; Review of etiologies and clinico-hematological profile at a tertiary center. Indian Journal of Pathology and Microbiology. 54(1), Jan-March 2011. PGI-Chandigarh 16

Lab Evaluation:

1. CBC WITH PERIPHERAL BLOOD SMEAR

2. BONE MARROW ASPIRATION AND BIOPSY

3. SPECIFIC INVESTIGATIONS 17

PERIPHERAL BLOOD SMEAR

Anisocytosis and poikilocytosisWBC and RBC precursorsPlateletsGranulation in neutrophils (Abnormally

increased/decreased)Neutrophils(Hypo/Hypersegmentation)ESR

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1. Anisocytosis & Poikilocytosis

MODERATE DEGREE IS COMMON

Very marked Poikilocytosis: MYELOFIBROSIS

Less degree: APLASTIC ANEMIA, MARROW INFILTRATION BY LYMPHOMA/MULTIPLE MYELOMA

Invariably absent: ACUTE LEUKEMIA19

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RBC INDICES

• RDW: Usually increased• MCV: Can be increased or normal• RETICULOCYTE COUNT- Define severity and

differentiate production vs. destruction

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2. WBC AND RBC PRECURSORS

Blast cells: MyelofibrosisAcute leukemiasSubleukemic leukemias

Plasmacytic cells: Multiple myeloma

Immature lymphocytes: Marrow involvement by lymphoma

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WBC AND RBC PRECURSORS ARE NOT TYPICAL OF APLASTIC

ANEMIA

SO THEIR PRESENCE IN PANCYTOPENIA SUGGEST DIAGNOSIS OTHER THAN

APLASTIC ANEMIA 23

RBC INCLUSIONS:HOWEL JOLLY BODIES

• Basophilic nuclear remnants (clusters of DNA) in RBCs• Megaloblastic anemia• MDS

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3. Platelets

• Normal Platelets: Aplastic Anemia

• Giant Platelets: MDS Hypersplenism

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4. ABNORMAL GRANULATION IN NEUTROPHILS

• Toxic granules: Infections

• Hypo granular neutrophils: MDS

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5. HYPO/HYPERSEGMENTATION IN NEUTROPHILS

• Hyper segmented Neutrophils: Megaloblastic Anemia

• Pelger Huet like cells: MDS,Chronic leukemias, Folate and B12 deficiency.

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HYPERSEGMENTATION

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6. ESR

• Increased in : InfectionsMultiple myeloma

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BONE MARROW EXAMINATION

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Bone Marrow Examination

Almost always indicated in cases of pancytopenia unless cause is apparent

Both aspiration and biopsy are indicated

Specifically, bone marrow aspirate permits examination of: • Cytology (megaloblastic change, dysplastic changes,

abnormal cell infiltrates) • Immunophenotyping : antigen or marker on cells

surfaces e.g ( leukemias, lymphoproliferative disorders) • Cytogenetics : structure of chromosome

(myelodysplasia, leukemias, lymphoproliferative disorders)

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Cellularity of Bone Marrow

The differential diagnosis of pancytopenia are based on cellularity of bone marrow :

Hypocellular: excessive amount of fat cells

Normocellular: 50-70% hematopoietic cells & 30-50% fat

Hypercellular: 80-100% cells with little fat

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HYPERCELLULAR

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Bone Marrow Examination findings

Features Seen inCELLULARITY HYPERCELLULAR: Megaloblastic anemia, Hyperslenism

DRY TAP: MyelofibrosisHYPOPLASTIC: Myelodysplastic syndromes

ERYTHROPOIESIS DYSPLASTIC: MDS, some AMLINCREASED: Hemolysis

MYELOPOIESIS DYSPLASTIC: Myelodysplastic syndromeMophologically normal: Myeloproliferating disorders

BLASTS Myelodysplastic disorders, Acute LeukemiasMEGAKARYOPOIESIS DYSPLASTIC: Myelodysplastic disorderOTHER CELLS Reedsternberg cell: Hodgkin cell

Bacteria, Fungus, Parasite, Viruses, LD bodies34

SPECIFIC INVESTIGATIONS

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TEST RATIONALEBONE X-RAYS Multiple myeloma, metastasis

BLOOD CULTURE Infectious agent- Tuberculosis or virus

VITAMIN B12 AND FOLATE ASSAYS Megaloblastic anemia

LFT Evaluate hepatitis

KFT Assess for Chronic Renal Failure

SEROLOGY HIV, EBV, Hepatitis

HAM’S TEST Paroxysmal Nocturnal Haemoglubinuria

CHROMOSOMAL BREAKAGE STUDIES

Fanconi anemia

ANA test Systemic Lupus Erythematosus36

Thanks for your Attention

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