1. Unexplained Anaemia Acute Medicine Update
Dr.Srinivasan Narayanan
Consultant in Haematology
University Hospital Southampton NHSFT

2. Introduction Common causes Rare causes Unexplained causes Summary
?Pathophysiology
Investigations
Treatment options
Summary

3. Common causes of Anaemia

4. Diagnosis

5. Diagnosis

6. Diagnosis

7. Anaemia of chronic disease
Impaired erythropoietin production
Blunted response of marrow to endogenous erythropoietin
Impaired iron metabolism mediated by inflammatory cytokines and stimulates liver production of hepcidin
Hepcidin reduces iron absorption and decrease iron release from macrophages
Normocytic, hypochromic anaemia with low iron binding capacity, normal or high ferritin and increased marrow iron

8. Myelodysplasia Most often in older age groups
Anaemia could be only presenting feature
Difficult to diagnose in early stages
Blood film may help
Bone marrow assessment is required to confirm the diagnosis
Epo<500 may respond to Epo injections

9. MDS

10. MDS

11. Rare causes Inherited Acquired
Haemoglobinopathy disorders eg.unstable Hb
Enzyme and membrane disorders
Congenital dyserythropoietic anaemias
Sideroblastic anaemias
Acquired
Aplastic anaemia
Paroxysmal nocturnal haemoglobinuria

12. Diagnosis?

13. Sideroblastic anaemia
Inherited and acquired causes
Mutation of genes in haem biosynthesis
Most common – ALA synthase gene mutation
Characterized by ring sideroblasts
Accumulation in perinuclear mitochondria within erythroblasts due to impaired iron utilisation
Acquired – MDS, alcohol, lead toxicity

14. Ring sideroblasts

15. Ring sideroblasts

16. Congenital dyserythropoietic anaemias
Rare congenital anaemias, 3 major subtypes
Mild to moderate anaemia due to ineffective erythropoiesis
Secondary iron overload due to increased iron absorption
Characteristic bone marrow changes and EM appearances of the erythroblasts

17. CDA-II

18. Diagnosis

19. Paroxysmal nocturnal Haemoglobinuria
Rare disease
Acquired mutation of PIG-A gene
Defect in the production of GPI protein anchors which protects against complement destruction
Increased red cell destruction

20. Normal Hematopoietic Cells
CD55
CD59
Normal Hematopoietic Cells
Transmembrane
protein
GPI anchors
Membrane lipid bilayer 20

21. PNH Hemolytic screen Flow cytometry Bone marrow biopsy Treatment:
Anticoagulation
Eculizumab – monoclonal antibody against C5
Bone marrow transplantation

22. Unexplained anaemia Commonly mild anaemia (1-2 g/dl low) Normocytic
Usually multifactorial

23. Is it common?

24. Prevalance of anaemia increases over 50, >20% at 85 years or older

26. Is it clinically relevant?

27. Retrospective cohort study of over 300000 patients 1997-2004
Age over 65 years undergoing non-cardiac surgery
3 groups: Hct<39, , >54
30 day mortality increase by 1.6% for every 1% change in Hct<39–Wu et al

28. Features of unexplained anaemia

29. Possible causes Age related renal insufficiency Chronic inflammation
pronounced decline in DM/HT
Chronic inflammation
Stem cell ageing
Reduced regenerative capacity
Androgen insufficiency
Shortened red cell survival

31. Investigations Blood film Reticulocyte count
Ferritin, STR, Haematinics
Haemolytic screen
Thyroid function
Erythropoietin level
Bone marrow biopsy

32. Erythropoietin MW 30400Da Discovered by Miyake et al in 1977
LC 4 alpha helical bundle class 1 cytokine

33. Erythropoietin
Renally secreted glycopeptide which stimulates erythropoiesis
Normally rises with anaemia
Blunted response in chronic inflammatory conditions, cancer, RA
Helps in reducing/avoid blood transfusions

34. Biology Epo stimulates erythropoiesis
Low oxygen supply increases the production of Epo
Produced by the interstitial cells in kidney

35. 32 week randomised, double blinded crossover trial with placebo and Epoetin alpha in elderly -Agnihotri P et al
62 patients with chronic anaemia

37. Increase in Hb>2 g/dl
Improvement in QOL studies

38. Monitor blood pressure, risk of hypertension
Avoid in patients with recent MI/CVA
Maintain Hb g/l, aim lower Hb level in patients with thrombocytosis, ischaemic vascular disease.
Responds better after iron/folate replacement in deficient patients.

39. ICUS
New terminology coined for unexplained cytopenias, persists for at least 6 months
Hb<110 g/l, with no clear reason
Acknowledgement of diagnostic uncertainty
Does not meet the diagnostic criteria for MDS or other conditions
Recommend long term monitoring as it may progress to MDS
Suboptimal Epo production could be the cause

40. Summary
Consider occult bleed, Anaemia of chronic disease or low grade haemolysis before UA.
Polypharmacy, inadequate nutrition, alcohol abuse also have a negative impact on erythropoiesis.
Associated neutropenia, low platelets are suggestive of bone marrow disorders.

41. Any Questions?