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Congenital

• Transcobalamin II deficiency—absence of the key B12 transport protein results in severe megaloblastic anaemia (will correct with parenteral B12).

• Congenital intrinsic factor deficiency—autosomal recessive, results in failure to produce intrinsic factor. Presents as megaloblastic anaemia up to age of 2 years and responds to parenteral B12.

• Inborn errors of metabolism—errors in folate pathways, also occurs in orotic aciduria and Lesch-Nyhan syndrome.

• Megaloblastosis commonly present in the congenital dyserythropoietic anaemias (O p450).

Acquired

• MDS—often present in sideroblastic anaemia (RARS).

• Acute leukaemia—megaloblastic-like erythroid dysplasia in AML M6.

• Drug induced—secondary to antimetabolite drugs including 6-mercap-topurine, cytosine arabinoside, zidovudine and hydroxyurea.

• Anaesthetic agents—transient megaloblastic change after nitrous oxide.

• Alcohol excess —may result in megaloblastic change in absence of measurable folate deficiency.

• Vitamin C deficiency—occasionally results in megaloblastic change.

Iron, folate or vitamin B12 deficiencies account for the majority of clinically significant deficiency syndromes resulting in anaemia. Anaemia is recognised as a complication in other vitamin deficiencies and in malnutrition.

gg Vitamin A deficiency

Produces chronic disorder like iron deficiency anaemia with 5 MCV and MCH.

Vitamin B6 (pyridoxine) deficiency

Can produce hypochromic microcytic anaemia; sideroblastic change may occur. Pyridoxine is given to patients on antituberculous therapy with iso-niazid which is known to interfere with vitamin B& metabolism and cause sideroblastic anaemia.

Vitamin C deficiency

Occasionally associated with macrocytic anaemia (± megaloblastic change in 10%); since the main cause of vitamin C deficiency is inadequate diet or nutrition there may be evidence of other deficiencies.

Vitamin E deficiency

Occasionally seen in the neonatal period in low birth weight infants — results in haemolytic anaemia with abnormal RBC morphology.

Starvation

Normochromic anaemia ± leucopenia occurs in anorexia nervosa; features are not associated with any specific deficiency; bone marrow is typically hypocellular.

Definition

Any situation in which there is a reduction in RBC life-span due to 4 RBC destruction. Failure of compensatory marrow response results in anaemia. gg Predominant site of RBC destruction is red pulp of the spleen.

Classification—3 major types

1. Hereditary vs. acquired

2. Immune vs. non-immune

3. Extravascular vs. intravascular

Hereditary cause suggested if history of anaemia refractory to treatment in infancy ± FH e.g. other affected members, anaemia, gallstones, jaundice, splenectomy. Acquired haemolytic anaemia is suggested by sudden onset of symptoms/signs in adulthood. Intravascular haemolysis—takes place in peripheral circulation cf. extravascular haemolysis which occurs in RES.

Hereditary

• Red cell membrane disorders e.g. HS and hereditary elliptocytosis.

• Red cell enzymopathies e.g. G6PD and PK deficiencies.

• Abnormal Hb e.g. thalassaemias and sickle cell disease, unstable Hbs.

Acquired-immune

Alloimmune

• RBC transfusion incompatibility

Acquired-non-immune

• Hypersplenism

• Prosthetic heart valves

• March haemoglobinuria

• Paroxysmal nocturnal haemoglobinuria Clinical features

Symptoms of anaemia e.g. breathlessness, fatigue. Urinary changes e.g. red or dark brown of haemoglobinuria. Symptoms of underlying disorder.

Confirm haemolysis is occurring

• Peripheral blood film—polychromasia, spherocytosis, fragmentation (schistocytes), helmet cells, echinocytes.

• 4 reticulocytes.

• 4 serum bilirubin (unconjugated).

Autoimmune

• Cold—Mycoplasma or EBV infection,

• Cold haemagglutinin disease (CHAD)

• Lymphoproliferative disorders

• Paroxysmal cold haemoglobinuria (PCH)

• Low/absent serum haptoglobin (bind free Hb).

• Schumm's test (for intravascular haemolysis).

• Urinary haemosiderin (implies chronic intravascular haemolysis e.g. 69 PNH).

Discriminant diagnostic features

Establish whether immune or non-immune—check DAT

?Immune if DAT +ve check IgG and C3 specific reagents—suggest warm and cold antibody respectively. Screen serum for red cell alloantibodies.

?Cold antibody present—examine blood film for agglutination, check MCV on initial FBC sample and again after incubation at 37°C for 2h. High MCV at room temperature due to agglutinates falls to normal at 37°C. Check anti-I and anti-i titres for confirmation. Check Mycoplasma IgM and EBV serology, and for presence of Donath Landsteiner antibody (cold reacting IgG antibody with anti-P specificity).

?Warm antibody present—IgG +ve DAT only suggestive—examine film for spherocytes (usually prominent), lymphocytosis or abnormal lymphs to suggest LPD. Examine patient for nodes.

?Intravascular haemolysis—check for urinary haemosiderin, Schumm's test.

?Sepsis—check blood cultures.

?Malaria—examine thick and thin blood films for parasites.

?Renal/liver abnormality—examine for hepatomegaly, splenomegaly, LFTs and U&E.

?Low platelets—consider TTP/HUS.

?Haemoglobinopathy—check Hb electrophoresis.

?Red cell membrane abnormality—check family history and perform red cell fragility test.

?Red cell enzyme disorder—check family history and do G6PD and PK assay. Note: enzymes may be falsely normal if reticulocytosis.

?PNH—check immunophenotyping for CD55 + CD59 (Ham's acid lysis test now largely obsolete).

Treatment

Treat underlying disorder. Give folic acid and iron supplements if low.

Gehrs, B.C. & Friedberg, R.C. (2002) Autoimmune hemolytic anemia. Am J Hemato!, 69, 258-271.

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