Approach to Pancytopenia Flashcards

Question

Primary Aplastic Anaemia-Idiopathic Laboratory Diagnosis

Answer 1

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

Answer 2

``` 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 ```

Answer 3

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

Answer 4

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

Answer 5

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

Answer 6

Symptomatic-As for idiopathic aplastic anaemia Androgens-Side-effects severe including virilisation and liver dysfunction Stem cell transplant-Only cure

Answer 7

Dyskeratosis Congenita Diamond-Blackfan syndrome Shwachman-Diamond syndrome Amegakaryocytic thrombocytopenia Thrombocytopenia with absent radii

Answer 8

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

Answer 9

Antibiotics Anti-inflammatory Anti-convulsants Anti-thyroids Anti-depressants Anti-diabetics Anti-malarial Others-Mebendazole

Answer 10

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

Answer 11

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

Answer 12

Macrocytosis

Answer 13

Megaloblastic anemia -Oval macrocytes, anisocytosis, tear drops Vit B12 or Folic acid deficiency Macrocytic anaemia with normoblastic erythropoiesis Stress erythropoiesis

Answer 14

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

Answer 15

``` Liver disease Ethanol toxicity Hypothyroidism Haematological malignancies Aplastic anaemias Chronic hypoxic lung disease ```

Answer 16

Haemolytic anaemia Recovery from anaemia or blood loss Haematinic treatment

Answer 17

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)

Answer 18

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

Answer 19

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 ```

Answer 20

Stomach Duodenum Terminal ileum

Answer 21

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)

Answer 22

Pancreatic enzymes create alkaline environment Cbl released from R-protein Cbl binds to IF to form the IF-Cbl complex

Answer 23

Vit B12-IF bind to cubulin/amnionless receptor on enterocyte Absorbed by endocytosis IF destroyed Cbl transported to portal circulation

Answer 24

From enterocyte Cbl enters the portal circulation Enters plasma bound to transcobalamin: - Also called transcobalamin II - Delivers vitamin B12 to bone marrow & other tissues

Answer 25

Enters cells through endocytosis-Cobalamin then metabolized to: *Methyl-cobalamin – Homocysteine → Methionine – Folate metabolism and DNA synthesis *Adenosyl-cobalamin – Methylmalonyl CoA → Succinyl CoA

Answer 26

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

Answer 27

Gastric Abnormalities Small bowel disease Pancreatitis Diet Agents that block or inhibit Inherited transcobalamin II deficiency

Answer 28

PERNICIOUS ANEMIA Gastrectomy/bariatric surgery Gastritis Autoimmune atrophic gastritis

Answer 29

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

Answer 30

Pancreatic insufficiency Agents that block or inhibit absorption

Answer 31

Strict vegans | Vegetarian diet in pregnancy

Answer 32

Neomycin Biguanides (eg, metformin) Proton pump inhibitors (eg, omeprazole) Histamine 2 receptor antagonists (eg, cimetidine) N2O anaesthesia inhibiting methionine synthase

Answer 33

``` 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 ```

Answer 34

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.

Answer 35

Nutritional Deficiency Malabsorption Drugs Increased Requirements

Answer 36

Substance abuse Alcoholism Poor dietary intake Overcooked foods Depressed patients Nursing homes

Answer 37

Celiac disease (sprue) Inflammatory bowel disease Infiltrative bowel disease Short bowel syndrome

Answer 38

Methotrexate Trimethoprim Ethanol Phenytoin

Answer 39

Pregnancy, lactation Chronic haemolysis Exfoliative dermatitis

Answer 40

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

Answer 41

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

Answer 42

FBC and Peripheral Smear Biochemistry-Blood(Urine) Investigation

Answer 43

Macrocytic anemia Pancytopenia Oval macrocytes Megaloblasts Hypersegmented neutrophils Very seldom – blasts

Answer 44

Vitamin B12 Serum vitamin B12 Metabolites – ↑ Serum homocysteine – ↑ Serum (and urinary) methylmalonic acid (MMA) Folate Serum folate Metabolites – ↑ Serum homocysteine – MMA normal

Answer 45

Vitamin B12: Diet Serum gastrin Intrinsic factor and/or parietal cell antibodies Endoscopy Folate: Diet Intestinal malabsorption Anti-transglutaminase and endomysial antibodies Duodenal biopsy

Answer 46

Common cause of Vitamin B12 deficiency Auto-immune disease caused by: – Anti-IF antibodies – Anti-parietal cell antibodies Under-diagnosed – Especially older patients

Answer 47

F >M Peak age 60 years Early greying of hair Associated with autoimmune disorders Blue eyes Blood group A

Answer 48

Vitiligo Myxoedema Hashimoto's Disease Thyrotoxicosis Addison's Disease Hypoparathyroidism/ Hypogammaglobulinemia/Carcinoma of the Stomach

Answer 49

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

Answer 50

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.

Answer 51

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

Answer 52

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

Answer 53

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

Answer 54

Lymphoma, usually indolent variants Acute and chronic leukaemia Myeloproliferative disorders Multiple myeloma and its variants Primary splenic tumours Metastatic solid tumours

Answer 55

Viral - hepatitis, infectious mononucleosis, cytomegalovirus Bacterial - salmonella, brucella, tuberculosis Parasitic - malaria, schistosomiasis, toxoplasmosis, leishmaniasis Infective endocarditis Fungal Hematologic (hypersplenic) states

Answer 56

Sarcoid Serum sickness Systemic lupus erythematosus Rheumatoid arthritis (Felty syndrome)

Answer 57

Storage disorders Infiltrative, nonmalignant Amyloid Langerhans cell histiocytosis Hemophagocytic lymphohistiocytosis

Answer 58

Acute and chronic haemolytic anaemias Sickle cell disease (children) Following use of recombinant human granulocyte colony-stimulating factor