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Haematology > Approach to Pancytopenia > Flashcards

Approach to Pancytopenia Flashcards

1
Q

Types of reductions in cells:

A

Red cells – Anaemia
– Male: <13.5 (14.0) g/dL
– Female: <11.5 (12.0) g/dL

White cells – Leukopenia
– WCC: <4.0 x 109 /L

Platelets – Thrombocytopenia
– Platelet count: < 150 x 109/L

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2
Q

Causes of the Cell reductions

A

Decreased Production

Increased destruction-can be a combination

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3
Q

Decreased Production

A
  1. Aplasia
  2. Nutritional deficiency
  3. Bone marrow infiltration
  4. Haematological malignancies
  5. Connective tissue disorders
  6. Paroxysmal nocturnal
    haemoglobinuria (PNH)
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4
Q

Aplasia

A

Aplastic anaemia/bone marrow

failure

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5
Q

Nutritional deficiency

A

Megaloblastic anaemia –

Vitamin B12 or folate

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6
Q

Bone marrow infiltration

A 
Metastases
• Infections
• Tuberculosis
• Overwhelming bacterial
infection
• Viruses
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7
Q

Haematological malignancies

A
  • Myelodysplasia
  • Myelofibrosis
  • Lymphoma
  • Myeloma
  • Acute leukaemia
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8
Q

Connective tissue disorders

A

Systemic lupus erythromatoses
• Rheumatoid arthritis
• Others

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9
Q

Increased Destruction

A

Splenomegaly
– Including hypersplenism

Connective tissue disorders*

Paroxysmal nocturnal haemoglobinuria*

*Can be associated with cytopenias
and can be a combination of reduced
production and increased destruction

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10
Q

Investigations

A

FBC &Diff

Peripheral smear

Reticulocyte count

Bone marrow

Other tests:
Vit B12 & folate

Liver function

Viral studies

Autoimmune studies

PNH screen

Radiological studies

Genetic studies

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11
Q

Peripheral Smear

A

Round macrocytes:
-Liver dysfunction, aplasia, haematologicalmalignancies etc.

Megaloblastic changes:

  • Oval macrocytes, anisocytosis, poikilocytosis, hypersegmented neutrophils
  • Platelets rarely <60-70 x 109 /L

Leukoerythroblastic reaction:
-Possible bone marrow infiltration

Dysplasia

Immature cells

Infective change:
-Toxic granulation, left shift, vacuolization

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12
Q

Reticulocyte Count

A

Normal value

Adults: 50 – 100 (150) x 109/L / 0.5-2%

Distinguish between marrow failure and peripheral
destruction

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13
Q

Bone Marrow Aspirate and Trephine

A

Hypocellular/Aplastic

Hypercellular

Infiltrations
– Granuloma
– Aggregates
– Malignant cells
– Metastases
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14
Q

Differential Diagnosis for Bone Marrow Aspirate

A

Hypercellular Bone Marrow

Hypocellular Bone Marrow

Connective tissue disorders may fit either side

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15
Q

Hypercellular Bone Marrow Differential Dx

A

Megaloblastic anaemia

Peripheral destruction

Splenomegaly

Myelodysplasia

  • Older patients
  • Leukoerythroblastic reaction
  • Blasts
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16
Q

Hypocellular Bone Marrow Differential Dx

A

Aplasia
-Primary or secondary

PNH

Myelofibrosis
-Primary or secondary

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17
Q

Hypocellular Marrow and Cytopenia

A

Aplastic Anaemia

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18
Q

Aplastic Anaemia:

Definition

A

Aplastic (Hypoplastic) anaemia

  1. Pancytopenia
  2. Bone marrow aplasia-Hypocellular bone marrow

Primary or secondary: Acquired or inherited

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19
Q

Aplastic Anaemia:

Pathogenesis

A

Reduction in the number of haematopoietic stem cells

– Remaining stem cells may be normal or abnormal

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20
Q

Aplastic Anaemia:

Types

A

Primary Aplastic Anaemia

  • Idiopathic acquired
  • Congenital/Inherited Bone Marrow Failure

Secondary Aplastic Anaemia

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21
Q

Primary Aplastic Anaemia:

Causes

A

Acquired
– Idiopathic

Congenital
– Fanconi anaemia
– Dyskeratosis congenita
– Others

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22
Q

Secondary Aplastic Anaemia:

Causes

A

Radiation

Chemicals/Toxins
-Benzene, organophosphates, DDT, organic solvents etc.

Drugs

  • Chemotherapy- Antimetabolites, Alkylating agents, etc.
  • Antibiotics – Chloramphenicol, sulphonamides etc.
  • Anticonvulsants/antidepressants
  • Anti-inflammatory drugs – gold, etc.

Viruses
– Non-A, -B, -C, -D, -E, -G hepatitis, EBV, HIV

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23
Q

Primary Aplastic Anaemia-Idiopathic

Etiology

A

Onset at any age:
-Peak incidence 30 years

Slight male predominance

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24
Q

Primary Aplastic Anaemia-Idiopathic

Clinical Features

A

Insidious onset

Symptoms related to cytopenias

  • Anaemia
  • Thrombocytopenia-Bruising, gum bleeding, menorrhagia, epistaxis
  • Infections

Lymphadenopathy and hepatosplenomegaly is NOT a
feature of aplastic anaemia
-If present, consider an alternative diagnosis

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25
Q

Primary Aplastic Anaemia-Idiopathic

Laboratory Diagnosis

A

Anaemia:

  • Normochromic, normocytic or macrocytic (round)
  • MCV 95-110fL
  • Reticulocyte count extremely low

Leukopenia:

  • Usually granulocytes only
  • Usually <1.5 x 109/L
  • Severe cases may also show a lymphopenia

Thrombocytopenia-Always present

Peripheral smear:
-No abnormal cells seen

Bone marrow:
-Hypoplasia
-Haematopoietic tissue replaced by fat-May show patchy haematopoiesis
-Prominent lymphocytes and plasma cells, relative to
reduction of other cells

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26
Q

Primary Aplastic Anaemia-Idiopathic

Treatment

A 
Supportive
– Transfusion – Red cell or platelets
• Should be leucoreduced and irradiated
– Especially if transplant is required or patient is on
immunosuppressive treatment
– Antibiotics if infections is suspected
• Specific
– Immunosuppressive treatment
• Antilymphocyte globulin (ALG)/Antithymocyte globulin (ATG)
– Horse/Rabbit
– Stem cell transplant
• HLA-matched sibling preferred
– Other
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27
Q

Fanconi Anaemia

Etiology

A

Autosomal recessive inheritance

Usually between 5 and 10 years-but can present up to 4th decade

10% risk of developing acute myeloid leukaemia (AML)

Increased risk of myelodysplasia (MDS)

Increased risk of solid tumours-often squamous cell lung carcinoma

Genetics: Heterogeneous
– 13 different genes: A, B, C, D1, D2, E, F, G, I, J, L, M, N
– FANCG: Common in African population
– FANCA: Common in Afrikaner population
– FANCC: Common in Jewish population

• Encoded proteins are part of a common pathway
– Protection against genetic damage
– Fanconi cells show high frequency of chromosomal
breakage

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28
Q

Fanconi Anaemia

Clinical Presentation

A

Growth retardation

Skeletal abnormalities (Microcephaly, absent radii or thumbs) also other general abnormalities

Renal tract (horse shoe or pelvic kidney)

Skin (Hyper- or hypopigmentation)

May show mental retardation

About 40% no abnormalities-Only progressive bone marrow aplasia

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29
Q

Fanconi Anaemia

Laboratory Diagnosis

A

Pancytopenia
-Anaemia and macrocytosis may precede neutropenia
and thrombocytopenia

Bone marrow may be normo- or hypocellular

Screening test-Chromosomal breakage studies

Definitive
-Gene studies – Specific gene

Conventional karyotyping
-Patient may have chromosomal abnormalities

TREATMENT
OTHER CONGENITAL

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30
Q

Fanconi Anaemia

Treatment

A

Symptomatic-As for idiopathic aplastic anaemia

Androgens-Side-effects severe including virilisation and liver dysfunction

Stem cell transplant-Only cure

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31
Q

Other Congenital Abnormalities

A

Dyskeratosis Congenita

Diamond-Blackfan syndrome

Shwachman-Diamond syndrome

Amegakaryocytic thrombocytopenia

Thrombocytopenia with absent radii

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32
Q

Secondary Aplastic Anaemia

Causes

A

Direct damage to bone marrow

  • Radiation
  • Cytotoxic therapy-Mostly temporary/Alkylating agents may cause chronic aplasia

Idiosyncratic drug reactions

  • Rare
  • Drugs not known to be cytotoxic
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33
Q

Secondary Aplastic Anaemia

Drugs Causes

A

Antibiotics

Anti-inflammatory

Anti-convulsants

Anti-thyroids

Anti-depressants

Anti-diabetics

Anti-malarial

Others-Mebendazole

34
Q

Secondary AA

Viral Infections

A

Viral hepatitis

  • Usually during/within a few months
  • Usually Non-A, -B, -C, -D, -E, -G hepatitis:Hepatitis A and C associated AA is rare

HIV

Other:
CMV, EBV

35
Q

Secondary AA

Haematological Malignancies

A

Myelofibrosis

Some lymphomas
• E.g. Hairy cell lymphoma, Hodgkin lymphoma, other non Hodgkin lymphomas.

Hypoplastic acute myeloid leukaemia or myelodysplasia-Rare

Presenting features of acute lymphoblastic leukaemia in children-Rare

36
Q

Hypercellular Marrow and Cytopenias

A

Macrocytosis

37
Q

Macrocytosis:

Classification

A

Megaloblastic anemia
-Oval macrocytes, anisocytosis, tear drops
Vit B12 or Folic acid deficiency

Macrocytic anaemia with
normoblastic erythropoiesis

Stress erythropoiesis

38
Q

Megaloblastic anemia
• Oval macrocytes,
anisocytosis, tear drops

A

Vit B12 or Folic acid deficiency
Drugs, e.g. folate antagonists
N2O

39
Q

Macrocytic anaemia with

normoblastic erythropoiesis

A 
Liver disease
Ethanol toxicity
Hypothyroidism
Haematological malignancies
Aplastic anaemias
Chronic hypoxic lung disease
40
Q

Stress erythropoiesis

A

Haemolytic anaemia
Recovery from anaemia or blood
loss
Haematinic treatment

41
Q

Macrocytosis

Drugs which cause Macrocytosis

A

HIV treatment:
-Reverse transcriptase inhibitors (e.g., stavudine [Zerit],
lamivudine [Epivir], zidovudine [Retrovir])

Anticonvulsants (e.g., valproic acid [Depakote], phenytoin [Dilantin])

Folate antagonists (e.g., methotrexate)

Chemotherapeutics (e.g., alkylating agents, pyrimidine, purine inhibitors)

Trimethoprim/sulfamethoxazole (Bactrim, Septra)

Biguanides (e.g., metformin [Glucophage]), cholestyramine(Questran)

42
Q

Megaloblastic Anaemia

A

Macrocytic anaemia with oval macrocytes

Bone marrow:
-Hypercellular
-Megaloblastic morphology
-Delayed maturation of nucleus relative to that of the
cytoplasm-Due to defective DNA synthesis

Most commonly caused by:
-Deficiency of VIT B12 (COBALAMIN) OR FOLIC ACID

43
Q

Vitamin B12/Cobalamin

A

Minimum daily requirement: 6 - 9 mcg/day

Total body stores: 2-5 mg (2000 – 5000 mcg)
– ~50% in the liver
– Takes years to develop deficiency

Synthesized in nature by micro-organisms

Found in foods of animal origin:
– Liver,
– Meat,
– Fish,
– Dairy products
44
Q

Vitamin B12 Absorption:

Location

A

Stomach

Duodenum

Terminal ileum

45
Q

Vitamin B12 Absorption:

Stomach

A

Acidic environment

Cbl released from food

Bind to R protein

IF secreted by parietal cells

Cbl: Cobalamin (Vitamin B12)
IF: Intrinsic factor
R: R-protein (R binder/R factor)

46
Q

Vitamin B12 Absorption:

Duodenum

A

Pancreatic enzymes create alkaline environment

Cbl released from R-protein

Cbl binds to IF to form the

IF-Cbl complex

47
Q

Vitamin B12 Absorption:

Terminal Ileum

A

Vit B12-IF bind to cubulin/amnionless receptor on
enterocyte

Absorbed by endocytosis

IF destroyed

Cbl transported to portal circulation

48
Q

Vitamin B12 Transport

A

From enterocyte Cbl enters the portal circulation

Enters plasma bound to transcobalamin:

  • Also called transcobalamin II
  • Delivers vitamin B12 to bone marrow & other tissues
49
Q

Vitamin B12 Metabolism

A

Enters cells through endocytosis-Cobalamin then metabolized to:

*Methyl-cobalamin
– Homocysteine → Methionine
– Folate metabolism and DNA synthesis

*Adenosyl-cobalamin
– Methylmalonyl CoA → Succinyl CoA

50
Q

Factors required for Vitamin B12 Absorption

A

Dietary intake

Acid-pepsin in the stomach to liberate Cbl from binding to proteins

Pancreatic proteases to free Cbl from binding to R factors

Secretion of intrinsic factor (IF) by the gastric parietal cells to bind to Cbl

An intact ileum with functional Cbl-IF receptors

51
Q

Causes of Vitamin B12 Deficiency

A

Gastric Abnormalities

Small bowel disease

Pancreatitis

Diet

Agents that block or inhibit

Inherited transcobalamin II deficiency

52
Q

Causes of Vitamin B12 Deficiency:

Gastric Abnormalities

A

PERNICIOUS ANEMIA
Gastrectomy/bariatric surgery
Gastritis
Autoimmune atrophic gastritis

53
Q

Causes of Vitamin B12 Deficiency:

Small bowel disease

A 
Malabsorption syndrome
Ileal resection or bypass
Crohn's disease
Blind loops
Diphyllobothrium latum (fish tapeworm)
TB of the distal ileum
54
Q

Causes of Vitamin B12 Deficiency:

Pancreatitis

A

Pancreatic insufficiency

Agents that block or inhibit absorption

55
Q

Causes of Vitamin B12 Deficiency:

Diet

A

Strict vegans

Vegetarian diet in pregnancy

56
Q

Causes of Vitamin B12 Deficiency:

Agents that block/inhibited absorption

A

Neomycin

Biguanides (eg, metformin) Proton pump inhibitors (eg,
omeprazole)

Histamine 2 receptor antagonists (eg,
cimetidine)

N2O anaesthesia inhibiting methionine
synthase

57
Q

Folate Description

A 
Found in most foods
– Highest concentration:
• Liver, Green leafy vegetables, Yeast
– Easily destroyed by heat
• Normal daily requirement:
– Unstressed individuals = 200 - 400 mcg/day
– Pregnancy/lactation/haemolysis = 500 - 800 mcg/day
• Deficiency rare in general population
– Flour fortified with folate
58
Q

Folate Absorption and Transport

A

Folate is ingested as folate polyglutamates and the it
is converted to methyltetrahydrofolate (M-THF).

M-THF is then absorbed through duodenum and
jejunum

Transported bound to albumin.

59
Q

Folate Deficiency:

Causes

A

Nutritional Deficiency

Malabsorption

Drugs

Increased Requirements

60
Q

Folate Deficiency:

Causes-Nutritional Deficiency

A

Substance abuse

Alcoholism

Poor dietary intake

Overcooked foods

Depressed patients

Nursing homes

61
Q

Folate Deficiency:

Causes-Malabsorption

A

Celiac disease (sprue)

Inflammatory bowel disease

Infiltrative bowel disease

Short bowel syndrome

62
Q

Folate Deficiency:

Causes-Drugs via various Mechanism

A

Methotrexate

Trimethoprim

Ethanol

Phenytoin

63
Q

Folate Deficiency:

Causes-Increased Requirements

A

Pregnancy, lactation

Chronic haemolysis

Exfoliative dermatitis

64
Q

Megaloblastic Anaemia:

Clinical Features

A

Insidious onset

Gradually progressive anaemia

Mild jaundice

Glossitis
– Beefy, painful, smooth red tongue

Angular stomatitis

Mild malabsorption symptoms
– May have loss of weight

Melanin pigmentation

ortant

65
Q

Megaloblastic Anaemia:

Neurological Manifestations

A

Vitamin B12

Neuropathy

Progressive neuropathy

  • Posterior and lateral columns
  • Symmetrical
  • Pain/ parasthesia in feet
  • Difficulty walking
  • Loss of proprioception

Optic atrophy

Psychiatric symptoms

Vitamin B12/Folate

Neural tube defects

  • Encephalocoele
  • Spina bifida
  • Anencephaly

Supplementation in pregnancy with folic acid
very important

66
Q

Megaloblastic Anaemia:

Diagnosis

A

FBC and Peripheral Smear

Biochemistry-Blood(Urine)

Investigation

67
Q

Megaloblastic Anaemia:

Diagnosis-FBC and PS

A

Macrocytic anemia

Pancytopenia

Oval macrocytes

Megaloblasts

Hypersegmented neutrophils

Very seldom – blasts

68
Q

Megaloblastic Anaemia:

Diagnosis-Biochemistry

A

Vitamin B12

Serum vitamin B12

Metabolites
– ↑ Serum homocysteine
– ↑ Serum (and urinary) methylmalonic acid (MMA)

Folate

Serum folate

Metabolites
– ↑ Serum homocysteine
– MMA normal

69
Q

Megaloblastic Anaemia:

Diagnosis-Investigation of Cause

A

Vitamin B12:

Diet

Serum gastrin

Intrinsic factor and/or parietal cell antibodies

Endoscopy

Folate:

Diet

Intestinal malabsorption

Anti-transglutaminase and endomysial antibodies

Duodenal biopsy

70
Q

Pernicious Anaemia:

Etioology

A

Common cause of Vitamin B12 deficiency

Auto-immune disease caused by:
– Anti-IF antibodies
– Anti-parietal cell antibodies

Under-diagnosed
– Especially older patients

71
Q

Pernicious Anaemia:

Clinical Presentation

A

F >M

Peak age 60 years

Early greying of hair

Associated with autoimmune disorders

Blue eyes

Blood group A

72
Q

Pernicious Anaemia Associations:

Female

Blue Eyes

Early Greying

Northern European

Familial

Blood Group A

A

Vitiligo

Myxoedema

Hashimoto’s Disease

Thyrotoxicosis

Addison’s Disease

Hypoparathyroidism/ Hypogammaglobulinemia/Carcinoma of the Stomach

73
Q

Schilling Test

A

Radiolabeled vitamin B12 measure % excreted in urine

Method:

Part I:

  • Oral radiolabelled B12
  • Non-radiolabelled IM dose
  • Collect 24 hour urine sample

Interpretation:
-Normal excretion:Inadequate dietary intake

-Reduced excretion:
Malabsorption
Pernicious anaemia

Part II:

Second test dose with intrinsic factor
-Pernicious anaemia:
Correction of absorption
-Malabsorption: No correction

Not often used/available at present-More historic value

74
Q

Pernicious Anaemia:

Treatment

A

Vitamin B12 supplementation:Lifelong

– 1000ug IM daily for one week
– 1000ug IM weekly for one month
– 1000ug IM 1-3 monthly, lifelong

Prophylactic
– Total gastrectomy
– Ileal resection

Folate supplementation

– 5mg daily PO for 4 months

Prophylaxis
– Pregnancy
– Severe haemolysis
– Dialysis
– Prematurity

Vitamin B12 deficiency should be excluded before treatment with folate is commenced to prevent aggravation of neurological symptoms.

75
Q

Hypersplenism

Description

A

Normal spleen:
Store ~5% of red cells and ~30% of platelets, 50% of marginated neutrophils

Enlarge spleen
– Increased sequestration
– Can sequestrate up to 90% of platelets

Definiton:
Presence of peripheral cytopenias with a enlarged spleen, bone marrow can be normal/hypercellular and the cytopenia is usually corrected when the spleen is removed

76
Q

Hypersplenism:

Causes

A

The underlying cause for the splenomegaly should be
investigated.

Consider bone marrow examination if cause is not
apparent.

Congestive

Malignancy

Infection

Infiltrative, Non-malignant

Haematologic(Hypersplenic) states

77
Q

Hypersplenism:

Causes-Congestive

A

Cirrhosis
Heart failure
Thrombosis of portal, hepatic, or splenic veins

78
Q

Hypersplenism:

Causes-Malignancy

A

Lymphoma, usually indolent variants

Acute and chronic leukaemia

Myeloproliferative disorders

Multiple myeloma and its variants

Primary splenic tumours

Metastatic solid tumours

79
Q

Hypersplenism:

Causes-Infection

A

Viral - hepatitis, infectious mononucleosis,
cytomegalovirus

Bacterial - salmonella, brucella, tuberculosis

Parasitic - malaria, schistosomiasis,
toxoplasmosis, leishmaniasis

Infective endocarditis

Fungal

Hematologic (hypersplenic) states

80
Q

Hypersplenism

Cause-Inflammation

A

Sarcoid

Serum sickness

Systemic lupus erythematosus

Rheumatoid arthritis (Felty syndrome)

81
Q

Hypersplenism

Cause-Infiltrative-Non-Malignant

A

Storage disorders

Infiltrative, nonmalignant

Amyloid

Langerhans cell histiocytosis

Hemophagocytic lymphohistiocytosis

82
Q

Hypersplenism:

Cause-Hypersplenic States

A

Acute and chronic haemolytic anaemias

Sickle cell disease (children)

Following use of recombinant human
granulocyte colony-stimulating factor

Haematology (10 decks)

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