Anaemia

Chan Sze qi
Chen Mi San
Shafiq Zahari
Learning Outcome
• Physiology of erythrocyte production & breakdown
• Entero-hepatic circulation
• Process of heme breakdown
• Markers of hemolysis in serum and urine
• Classification, clinical features, investigation and management of haemolytic anaemia
• Aetiology, pathogenesis, clinical features, complications, investigations and management
of iron deficiency anaemia.
• Aetiology, pathogenesis, clinical features, complications, investigations and management
of megaloblastic anaemia.
• Aetiology, pathogenesis, clinical features, complications, investigations and management
of aplastic anaemia.
Physiology of Erythrocyte
Production & Breakdown
Chan Sze Qi
Erythrocyte production
• When renal interstitial peritubular cells detected
hypoxia, it produces erythropoietin, to stimulate
proliferation and differentiation of red cell
precursors.
• Red cell precursors (erythroblasts) divide and
acquire hb, which turns the cytoplasm pink; the
nucleus condenses and is extruded from the cell.
• Non-nucleated cell is a reticulocyte, it contains
ribosomal material in cytoplasm, giving these large
cells a faint blue tinge (polychromasia).
• Reticulocytes lose their ribosomal material and
mature over 3 days, during which time they are
released into the circulation.
• Increased number of circulating reticulocytes
reflect increased erythropoiesis.
Breakdown of erythrocyte
• Red cells have lifespan of approx. 120 days.
• At the end of their lifespan, they are phagocytosed
by reticulo-endothelial system.
• Amino acids (from globin chain) – are recycled.
• Iron (from haem) – are reused in haemoglobin
synthesis.
• Remnant haem structure – degraded to bilirubin
and conjugated with glucuronic acid – then
excreted in bile.
• In small bowel, bilirubin is converted into
stercobilin; most of this is excreted, but a small
amount is reabsorbed and excreted by the kidney
as urobilinogen.
• Increased red cell destruction due to haemolysis or
ineffective haematopoiesis results in jaundice and
increased urinary urobilingen.
• Free intravascular hb is toxic. It is normally bound
by haptoglobins (plasma protein that produced by
liver).
Enterohepatic circulation
• Bilirubin that excreted in the bile that enters small
bowel, if they are sufficiently lipid-soluble, be
reabsorbed through gut wall and return to liver via
portal vein.
• This recycling between the liver, bile, gut and
portal vein is known as ‘enterohepatic circulation’.
Haemolytic Anaemia
Shafiq Zahari
Classification of Haemolytic Anaemia
• Inherited
• Red cell membrane abnormality
• Hereditary Spherocytosis
• Hereditary Eliptocytosis
• Red cell enzyme deficiency
• Pyruvate Kinase (Glycolysis)
• G6PD (Hexose Monophosphate Shunt)
• Pyrimidine 5’ Nucleotidase (RNA Degradation in Reticulocytes)
• Haemoglobin
• Thalassaemia (Deficiency)
• Sickle-cell Disease (Abnormality)
 Classification of Haemolytic Anaemia
• Acquired
• Immune • Non Immune
• Autoantibodies
• Warm Antibodies
• Mechanical
• Idiopathic, SLE, RA, L-dopa, methyldopa, • Prosthetic valves, DIC, HUS, TTP, March
mefenamic acid, penicillin, quinidine, Haemoglobinuria
fludarabine, CLL, Myeloma, Lymphoma, • Infection
Lung CA, Colon CA, Kidney CA, Ovary CA,
Thymoma, Ulcerative Colitis, HIV • Malaria, C. perfringens
• Cold Antibodies • Chemical/Physical
• Idiopathic, Mycoplasma, EBV, Syphilis, • Dapsone, Maloprim, Wilson’s Disease, Burns,
Lymphoma
Drowning
• Alloantibodies
• Red Cell Antigen Induced • Acquired Abnormal Membrane
• Transfusion Reaction, Haemolytic Disease • Paroxysmal Nocturnal Haemoglobinuria
of Newborn
Hereditary Spherocytosis
• Autosomal Dominant
• Deficiency in beta spectrin and ankyrin
• Presentation - asymptomatic compensated chronic haemolytic state with
spherocytes on blood film, Reticulocytosis and mild hyperbilirubinaemia.
• Investigations – screening for family, variable level of haemoglobin, shows
spherocytes, negative Coombs test, osmotic fragility test shows sensitivity
to lysis, flow cytometric test detecting binding of eosin-5-maleimide to red
cells in borderline cases
• Management – Folic Acid prophylaxis 5mg daily for life, splenectomy if
indicated and more than 6 years of age in view of risk in sepsis, sever
haemolytic crisis may require transfusion support.
Hereditary Elliptocytosis
• Autosomal Dominant or Recessive
• Less common than spherocytosis
• Characteristic variant in southeast asia particularly Malaysia and
Papua New Guinea with stomatocytes and ovalocytes in blood.
• Offers relative protection towards Malaria
• If presented with asymptomatic abnormal blood film but occasional
cases result in neonatal haemolysis or a chronic compensated
haemolytic state.
• Management are same with hereditary spherocytosis.
G6PD
• Glucose-6-phosphate dehydrogenase (G6PD) takes part in glucose
metabolism pathways in red cell.
• More common in males than in females.

• Clinical features:
• Anemia
• Jaundice
• Hemoglobinuria
RBC Metabolic Abnormalities – G6PD
Deficiency
• Clinical syndromes:
• Acute drug-induced hemolysis
• Favism (ingestion)
• Chronic haemolytic anemia
• Neonatal jaundice
• Infections and acute illness – precipitate
hemolysis in G6PD deficiency
• Mothballs containing naphthalene – cause
hemolysis
RBC Metabolic Abnormalities – G6PD
Deficiency
Investigations Treatment
• Blood count • Stop any offending drugs
• Between attack – normal • Treat underlying infection
• During attack – irregularly
contracted ells, bite cells, blister • Blood transfusion may be life-
cells, Heinz bodies and saving
reticulocytes
• Screening test • Splenectomy is not usually
• Demonstration of the decreased helpful.
ability of G6PD-deficient cells to
reduce dyes.
Pyruvate Kinase Deficiency
• Second most common red cell enzyme defect.
• Deficiency in ATP production and a chronic haemolytic anaemia
• Autosomal Recessive
• Blood film shows prickle cells
• Transfusion support may be needed during periods of haemolysis.
Hemoglobinopathies – SCD
• Deoxygenated HbS molecules are insoluble and polymerize
• Flexibility ↓ and they become rigid and become sickle cell

• Clinical features:
• Anemia
• Vaso-occlusive crises
• Pulmonary hypertension
• Acute chest syndrome
• Splenic sequestration
• Bone marrow aplasia
• Long term problems – growth and development
Hemoglobinopathies – SCD
• Investigations:
• Blood count
• Hb 60-80g/L, high reticulocytes (10-20%)

• Blood film
• Features of hyposplenism and sickling

• Sickle solubility test

• HbS + reducing solution (e.g sodium dithionite) = turbid apprearance

• Hb electrophoresis
Hemoglobinopathies – SCD
• Management
• Acute painful attacks
• supportive therapy with intravenous fluids and
adequate analgesia.
• Painful and quite strong – morphine
• Milder pain – codeine, paracetamol and NSAIDs
• Prophylaxis
• Penicillin 500mg daily
• Vaccination with polyvalent pneumococcal and
Haemophilus Influenza type b vaccine
• Folic acid
• Given to all patient with hemolysis
Beta Thalassaemia
• Failure to synthesizes beta chains
• Cure available for selected children
with allogeneic HSCT
Alpha Thalassaemia
• Reduced or absent alpha-chain synthesis is common in Southeast
Asia.
• One is deleted – no clinical effect
• Two are deleted – mild hypochromic anaemia
• Three are deleted – Haemoglobin H disease
• Four are deleted – hydrops fetalis
• Management
• Folate supplementation
• Transfusion if required
• Avoidance of iron therapy
Autoimmune hemolytic anemia
• Results from increased red cell destruction.

• 2 distinct mechanisms:
i. True autoantibody against RBC antigen
ii. RBC getting caught and destroyed during the reaction between
antigen directed at another molecule.

• Divided into ‘warm’ and ‘cold’ types depending on the optimum

temperature at which the antibody is active (thermal specificity)
Clinical Features
• Abrupt onset of anemia
• Hemoglobin can drop to as low as 4 g/dL – leads to jaundice
• Spleen may be enlarged
• Hemoglobinuria – if there is intravascular hemolysis.
Investigations
• Full blood count & peripheral blood film
• Hemolytic anemia
• Spherocytosis – due to red cell damage.
• Thrombocytopenia and/or neutropenia may also be present.

• Direct antiglobulin test is positive

Management
1. In emergency setting, red cell transfusion is given (eventhough incompatible)

2. If not life threatening, prednisone is given – to induce remission.

3. Can combine low dose Rituximab + prednisone

4. If there is relapse/refractory to medical treatment – splenectomy is

considered.
Alloimmune hemolytic anemia

• Antibodies produced in one individual react with the red cells of

another.
• Causes:
• Hemolytic transfusion reaction
• Hemolytic disease of the newborn
Hemolytic transfusion reaction
• It is usually due to ABO incompatibility.
• There is complement activation by the antigen–antibody reaction,
usually caused by IgM antibodies.
Clinical features

• Rigors
• Lumbar pain
• Dyspnea
• Hypotension,
• Hemoglobinuria
• Renal failure.
• The initial symptoms may occur a few minutes after starting the
transfusion.
• Activation of coagulation also occurs and bleeding due to disseminated
intravascular coagulation (DIC) is a bad prognostic sign.
Investigations and Management
• To confirm where the error occurred, blood grouping should be
carried out on:
• the patient's original sample (used for the compatibility testing)
• a new sample taken from the patient after the reaction
• the donor units.
• At the first suspicion of any serious transfusion reaction, the
transfusion should always be stopped.
• Emergency treatment for shock is needed to maintain the blood
pressure and renal function.
Hemolytic disease of the newborn
• Caused by fetomaternal incompatibility for red cell antigens.
• Maternal alloantibodies against fetal red cell antigens pass from the
maternal circulation via the placenta into the fetus, where they
destroy the fetal red cells.
• The most common type of HDN is that due to ABO incompatibility,
where the mother is usually group O and the fetus group A.
Clinical Features
• Vary from a mild hemolytic anemia of the newborn to intrauterine
death from 18 weeks' gestation due to hydrops fetalis.
• Kernicterus - severe jaundice in the neonatal period and bile pigment
deposition occurs in the basal ganglia.
• This can result in permanent brain damage, choreoathetosis and
spasticity. In mild cases, it may present as deafness.
Investigations & Management

Investigations Management
• Routine antenatal serology • Phototherapy in mild cases
• Antenatal assessment & treatment • Exchange transfusion may be
needed in severe cases to to
replace the infant's red cells and to
• Birth of an affected infant remove bilirubin.
• A sample of cord blood is obtained
at birth.
• anemia with a high reticulocyte count
• a positive direct antiglobulin test
• a raised serum bilirubin.
Drug-induced immune hemolytic anemia

• The interaction between a drug and red cell membrane may produce
three types of antibodies:

• Antibodies to the drug only - e.g. quinidine, rifampicin.

• Antibodies to the cell membrane only - e.g. methyldopa, fludarabine.

• Antibodies to part-drug, part-cell membrane - e.g. penicillin

• Confirmation of the diagnosis of drug-induced immune
hemolytic anemia requires:
• A temporal association between administration of a drug and
hemolytic anaemia.
• Recovery after withdrawal of the drug.
• A positive direct antiglobulin test.
• Drug-dependent red cell antibodies.
Mechanical hemolytic anemia

• Characterised by the presence of red cell fragments on the blood film and
markers of intravascular hemolysis:

a) Mechanical heart valves.

High flow through incompetent valves or periprosthetic leaks results in shear stress
damage.

b) March hemoglobinuria.
Vigorous exercise can cause red cell damage in the capillaries
in the feet.
c) Microangiopathic hemolytic anemia
Fragmentation of red cells occurs in an abnormal microcirculation because of
malignant hypertension, eclampsia, hemolytic uremic syndrome

d) Thermal injury
Severe burns cause thermal damage to red cells, characterized by fragmentation
and the presence of microspherocytes in the blood.
 Infection
a) Plasmodium falciparum malaria
• may be associated with intravascular hemolysis and hemoglobinuria
(blackwater fever).

b) Clostridium perfringens septicemia

• Bacterial production of a lecithinase which destroys the red cell
membrane.
Chemicals or drugs

• Dapsone and sulfasalazine - hemolysis by oxidative denaturation of

hemoglobin.

• Other chemicals:
• Arsenic gas, copper, chlorates, nitrites and nitrobenzene derivatives.
Paroxysmal nocturnal hemoglobinuria (PNH)

• PNH is an acquired chronic HA characterized by triad of

1. Persistent intravascular hemolysis subject to recurrent

exacerbations
2. Pancytopenia
3. Tendency to venous thrombosis
Clinical Features
• Hemoglobinuria - only the urine voided at night and in the morning on waking is
dark in colour

• Recurrent attacks of severe abdominal pain

• Some patients present insidiously with signs of anemia

• Venous thrombotic episodes may occur at atypical sites

Investigations

• Intravascular haemolysis is evident.

• Flow cytometric analysis of red cells with anti-CD55 and anti-CD59 is
undertaken.
• Bone marrow is sometimes hypoplastic (or even aplastic) despite
hemolysis.
Management
• Blood transfusions in severe anaemia.
• Eculizumab
• It reduces intravascular hemolysis, hemoglobinuria and the need for
transfusion, and gives an improved quality of life.
• Long-term anticoagulation
• Bone marrow transplantation
Nutritional Anaemia -
Iron Deficiency Anaemia
Chen Mi San
Causes
● Increase demand - pregnancy, growth
● Blood loss, abnormal or excessive menstrual bleeding
● Decrease absorption - postgastrectomy
● Poor intake
● cervical carcinoma
● old male - bleeding hemorrhoids, barefoot walking hookworm infestation in
developing country, peptic ulcer disease, colon carcinoma
Clinical features
1. Glossitis (depapillated tongue)
2. Angular stomatitis
3. Koilonychia
4. Brittle nails
5. Brittle hair
6. Plummer-Vinson syndrome (dysphasia+glossitis)
Investigation
1. FBC - low hemoglobin
2. PBF - microcytic hypochromic, target cell, poikilocytosis, anisocytosis
3. Iron profile - low serum iron, low serum ferritin, high total iron binding
capacity (TIBC), high serum soluble transferrin receptor
4. Causes - proctoscopy, endoscopy, per rectal examination
Treatment
1. Iron replacement therapy
○ transferrin serum iron saturation (TSAT) <20% - IV
○ Transferrin serum iron saturation (TSAT) >20% - oral ferrous sulphate

2. Blood transfusion - hemoglobin <7g/dL

3. Treat causes
 Nutritional anemia
Megaloblastic anemia
Clinical features
1. angular stomatitis (painful)
2. glossitis (painful)
3. vB12 deficiency - neuropathy
Investigation
1. FBC - low hemoglobin
2. PBF - macrocytic hyperchromic anemia, hypersegmented neutrophil
3. Serum folate / serum vB12 low
4. Serum bilirubin high - destruction life developing cells
Management
1. vB12 deficiency
○ Hydroxocobalamine
○ Oral vB12
2. Folate deficiency
○ Oral Folic acid
○ Blood transfusion - hemoglobin <7g/dL
Aplastic anemia
Clinical features
1. anemia
2. Recurrent infections
3. Bleeding - initial presentation with bruising, blood blisters in mouth
4. Ecchymoses
5. Bleeding gums
6. Epistaxis
7. Mouth infections
Investigation
1. FBC
○ low RBC, low WBC, low platelet (pancytopenia, bicytopenia)
○ absent of reticulocytes
2. PBF
○ normocytic normochromic
3. Bone marrow study
○ FNAC, trephine biopsy
○ increase fat spaces
Management
1. Immunosuppressive treatment
2. Blood transfusion - hemoglobin <7g/dL
3. Bone marrow transplantation