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Approach to a case of pancytopenia (for pathologists)
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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
Bone Marrow Aspiration
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
Macrocytes, target cells, stomatocytes, acanthocytes
Macrocytes, target cells, stomatocytes, acanthocytes
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
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
Bone Marrow Aspiration
Hypercellular, erythroid hyperplasia
Hypercellular, erythroid hyperplasia
Hypercellular, erythroid hyperplasia
Hypercellular, erythroid hyperplasia