pancytopenia approach

Dr Vishu P BhasinDCP Resident, Santosh Medical College

Approach to a Case of Pancytopenia

Pancytopenia is a reduction in the number of

RBCs, WBCs and, platelets

in the peripheral blood below the lower limits of the age-adjusted

normal range for healthy people.

Therefore it is the combination of anemia, leukopenia, and thrombocytopenia :- Hb < 13.5 in males & 11.5 in females Leucocyte count < 4x109 /l Platelet count < 150x109 /l

It may result from decreased production of blood cells or

bone marrow failure, Defective stem cells, from their immune-mediated destruction or non-immune-mediated sequestration in the

periphery, Deficiency of factors stimulating

haematopoiesis

• The diagnosis is made from the results of CBC, preferably automated and a P/S

With Hypocellular marrow Cellular marrow with deficiency & systemic disease

Cellular marrow with primary bone marrow disease

Acquired aplastic anemia Vitamin B12 & Folic Acid Deficiency

Aleukemic Leukemia

Inherited Bone Marrow Failure syndromes

Hypersplenism Myelodysplastic syndrome

Hypocellular myelodysplastic syndrome

Kala Azar Myelofibrosis

Hypocellular acute leukemia SLE, Sjogrens Syndrome, Sarcoidosis

PNH

Paroxysmal Nocturnal Haemoglobinuria

TB, Brucellosis Marrow Necrosis

GVHD Metastatic Solid Tumor

Lymphoma Alcoholism

Myelofibrosis Storage Disease

Infections : Mycobacterial Infections

Gelatinous transformation of bone marrow

Chemotherapy & Drugs

Aplastic crisis in hemolytic anemia

Congenital / Inherited Mechanism : Decreased Marrow Production

Conditions Gaucher’s Disease Fanconi’s Anemia

• Acquired▫ Mechanism : Decreased Marrow Production

• Conditions ▫ Cytotoxic Chemotherapy▫ Radiation Therapy▫ Megaloblastic anemia▫ Bone Marrow Infiltration▫ Myelodysplasia▫ Myelofibrosis▫ Idiopathic Aplastic Anemia

Acquired Mechanism : Increased

destruction/Sequestration Conditions

Liver disease Portal hypertension

Acquired Mechanism : Increased

destruction/Sequestration + Decreased Marrow Production

Conditions Connective tissue disorders like SLE,

Rheumatoid Arthritis Acute Viral Infections like CMV, EBV, HIV HIV Infections Mycobacterial disease

Congenital Mechanism : Decreased Marrow Production

Conditions Various childhood metabolic & complex

multisystem disorders & inherited bone marrow failure syndromes

(ex dyskeratosis congenita, congenital amegakaryocytic thrombocyotopenia, Shwachman Syndrome)

Acquired Mechanism : Decreased Marrow Production

Conditions PNH Anorexia nervosa Transfusion associated – GVHD Heavy metal poisoning Infection – Parvo virus B19, HHV6 or CMV

in transplant recipients, Legionnaire disease)

Acquired Mechanism : Increased destruction

sequestration Conditions

Hypersplenism secondary to myelolymphoproliferative disorders

Hemophagocytic syndromes Drug induced immune pancytopenia Evans syndrome with tricytopenia Infection (brucellosis, visceral leishmaniasis)

History Clinical Examination CBC Peripheral smear examination Bone Marrow Aspiration Bone Marrow Biopsy Other specific investigations

Mild pancytopenia is often symptomless and detected incidentally when a full blood count/CBC is performed for another reason.

Duration of symptoms H/o Transfusions H/o Haemoglobinuria Dietary history Socio economic status Exposure to –

Drugs Anti cancer, Antibiotic, Anti epileptics, Anti thyroid (Aplastic) Barbiturates, Phenytoin, OCP ( B12 & FA)

Chemicals (Aplastic) Radiation (Aplastic) Infections (Aplastic)

Weight loss, fever – malignancy & inflammatory Jaundice – Hep B & C Infections – TB, Malaria Joint Pain – SLE Blood Loss

• A thorough physical exam is required, preferably by a hematologist.

• Weight loss and/or anorexia are harbingers of underlying infection (either precedent to the pancytopenia or as a result of it) and malignancy.

• Spontaneous mucosal bleeding (gums, GI tract), petechiae, and purpura with easy bruising secondary to thrombocytopenia are usually the first signs to develop directly related to more severe pancytopenia.

• These signs are often accompanied by lymphadenopathy (underlying infection, mononucleosis, lymphoproliferative disorder, and malignancy).

• Abdominal discomfort is a common presentation of splenomegaly and associated conditions.

• Widespread bone pain and loss of height suggest myeloma, joint pain systemic lupus erythematosus (SLE), and sore throat mononucleosis.

The following reference points to specific organ systems and associated conditions and is helpful to guide the examination.

• Eye examination▫ Retinal hemorrhage (thrombocytopenia)▫ Leukemic infiltrates (acute leukemia)▫ Jaundiced sclera (paroxysmal nocturnal hemoglobinuria, hepatitis, cirrhosis)▫ Epiphora (dyskeratosis congenita)

• Oral examination▫ Oral petechiae or hemorrhage (thrombocytopenia)▫ Stomatitis or cheilitis (neutropenia, vitamin B12 deficiency)▫ Gingival hyperplasia (leukemia)▫ Oral candidiasis or pharyngeal exudate (neutropenia, herpes family virus infections)

• Cardiovascular examination▫ Tachycardia, edema, congestive cardiac failure (all signs of symptomatic anemia)▫ Evidence of prior cardiac surgery (cardiac disease associated with congenital

syndromes)▫ Respiratory examination▫ Clubbing (lung cancer)▫ Tachypnea (sign of symptomatic anemia)

• Abdominal examination▫ Right upper quadrant tenderness (hepatitis)▫ Lymphadenopathy (infection, lymphoproliferative disorder, HIV disease)

• Signs of chronic liver disease▫ Splenomegaly (infection, myeloproliferative and lymphoproliferative

disorders)▫ Skin examination▫ Malar rash (SLE)▫ Purpura/bruising (thrombocytopenia)▫ Reticular pigmentation, dysplastic nails (dyskeratosis congenita)▫ Hypopigmented areas

• Hyperpigmentation, café au lait (Fanconi anemia)• Musculoskeletal examination

▫ Short stature (Fanconi anemia, other congenital syndromes)▫ Swelling/synovitis (SLE)▫ Abnormal thumbs (e.g., Fanconi anemia)

• Signs associated with HIV disease▫ Morbilliform rash early▫ Kaposi sarcoma, ulcerating nodules later

• A CBC and examination of peripheral blood film by a hematologist are essential. A standard battery of evaluative tests may include:▫ Serum reticulocyte count▫ Serum LFTs ▫ Hepatic serology▫ Serum coagulation profile, bleeding time,

fibrinogen, and D-dimer▫ Serum direct antiglobulin test▫ Serum B12 and folate▫ Serum HIV and nucleic acid testing.

Red Cell Morphology Normocytic normochromic with no anisopoikilocytosis, few macrocytes, no

nRBCs, reticulocytopenia – Aplastic anemia Macro ovalocytes with Howell Jolly Bodies – Megaloblastic anemias Tear drop cells, HJ bodies & Basophilic stippling – MDS nRBCs, Sickle cells – Aplastic crisis in Hemolytic anemiaWBCs Leucopenia (mostly mature ~80%) – Aplastic anemia Neutrophils present in increased number with toxic granules, shift to left –

Infections Basophilic stippling, hypersegmented neutrophils – Megaloblastic anemia Blasts – subleukemic leukemia Hypogranular neutrophils, pseudo Pelger Heut Anomaly – MDSPlatelets Normal count – rules out aplastic anemia Giant platelets – MDS/ Hypersplenism

• Examination of bone marrow is almost always indicated in cases of pancytopenia unless the cause is otherwise apparent (e.g., established liver disease with portal hypertension).

• The bone marrow exam consists of both an aspirate and a trephine biopsy,

• The differential diagnosis of pancytopenia may be broadly classified based on the ▫ bone marrow cellularity (reduced cellularity indicates decreased production of blood cells, ▫ whereas normal/increased cellularity indicates ineffective production or increased

destruction or sequestration of blood cells).

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

infiltrates, hemophagocytosis, and infection [e.g., Leishman-Donovan bodies])

• Immunophenotyping (acute and chronic leukemias, lymphoproliferative disorders)

• Cytogenetics (myelodysplasia, acute and chronic leukemias, lymphoproliferative disorders).

Aspiration Empty particles, markedly hypocellular, only

scattered mature lymphocytes & sometimes excess plasma cells – aplastic anemias

Pockets of cellularity with widespread hypocellularity – evolving aplastic anemia

Hypocellular with BM Blasts (>20%) – hypoplastic leulemia

Hypocellular BM with dysplastic megakaryocytes – hypoplastic MDS

Scattered proerythroblasts with large nuclear inclusions in hypocellular BM - Parvovirus

Biopsy Erythroid hyperplasia with megablastosis –

megaloblastic anemia Trilineage dysplasis with ringed sideroblasts

on pearl’s stain – MDS Infiltration by RS Cells – HL Infiltration with malignant cells – metastasis In PNH & Fanconi’s anemia – early stage will

show hypercellular normal appearing marrow

• Specific testing pinpoints diagnosis in the following conditions:▫ Fanconi anemia: diepoxybutane (DEB) test for chromosomal

breakage in peripheral blood lymphocytes▫ Lymphoproliferative disorders: immunophenotyping,

cytogenetics, lymph node biopsy▫ Multiple myeloma: immunoelectrophoresis▫ Paroxysmal nocturnal hemoglobinuria (PNH): peripheral blood

immunophenotyping for deficiency of phosphatidylinositol-glycan-linked molecules on peripheral blood cells (e.g., CD55, CD59)

▫ CMV infection: serum IgM and IgG▫ Epstein-Barr: serum monospot, viral capsid antigen (VCA), and

Epstein-Barr nuclear antibody (EBNA)▫ Leishmaniasis and other rare infections: blood and bone

marrow culture, serum ELISA▫ Rare genetic and metabolic disease: leukocyte

glucocerebrosides▫ Serum PSA in suspect cases of prostatic malignancy.

Pancytopenia

History, Examination, CBC, P/s, Retic count, Iron / TIBC

Palpable spleenWith incretic

Sepsis/BleedingBlasts / HypogranularPMN Unexplained

splenomegaly,M Band,Metastasis

No specificfinding

Hyper segmented neutrophils, Markedanisopoikilocytosis

B12 & Folic Acid LevelsHyper splenism, Malaria,

Leishmania

Bone Marrow Aspiration & Biopsy

HIV Antibody

NormalLow

Trial of therapy

No response

Chemotherapy & Radiotherapy

Vit B12 & Folic Deficiency Marrow Metastasis

Peripheral Blood Anisocytosis, Poikilocytosis, Basophilic Stippling

Oval macrocytic RBCs, Irregular size & shape of RBCs, hypersegmented neutrophils (>5 lobes)

Leuko erythroblastic cell forms

Reticulocyte Count Usually low Clumps of tumor cells

Bone Marrow Aspiration

Variable hypoplasia Hypercellular, megaloblastic erythoblasts, giant metamyelocytes

Bone Marrow Biopsy

Hypoplasia, Magaloblastosis

Vit B12 & FA Depend on dietary status, usually normal

VB12 and FA low in respective deficiencies

LDH Normal Moderately raised

LFT Normal Bil (I) Raised Raised ALT & AST

Other Investigations

Prolonged PT, PTT & D Dimer, Low fibrinogen

X Ray, CT, PSA, Thyroid USG, Mammography

NHL CLL Myelodysplasia

Peripheral Blood Variable, Circulating lymphoma cells

Circulating leukemia cells

Irregular or macrocytic RBCs, dysplastic granules, megakaryocytes


Increased proportion of lymphoid cells

Increased proportion of lymphoid cells

Hypercellular, rarely hypocellular, dysplastic changes

Immunophenotyping

Clonal population of lymphoid cells

Clonal population of lymphoid cells

LN Biopsy Lymphoproliferative disorder

Lymphoproliferative disorder

Reticulocytes Usually Low, May be N or Inc

Cirrhosis Hep B Hep C AIH

Peripheral Blood

Macrocytes, target cells, stomatocytes, acanthocytes




Reticulocytes Inc or N Inc or N Inc or N Inc or N

LFT Elevated – AST, ALT, GGT

Elevated – AST, ALT, GGT



Viral Serology HCV +ve in HCV cirrhosis

HBsAg+VE HCV +ve in HCV cirrhosis

ANA, LKM, ASMA +ve


Hypercellular, erythroid hyperplasia




pancytopenia approach

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