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
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
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
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
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
Normal Hematopoietic Cells Membrane lipid bilayer Transmembrane protein CD55CD59 GPI anchors
PNH Hemolytic screen Flow cytometry Bone marrow biopsy Treatment: Anticoagulation Eculizumab – monoclonal antibody against C5 Bone marrow transplantation
Prevalance of anaemia increases over 50, >20% at 85 years or older
Is it clinically relevant?
Retrospective cohort study of over patients Age over 65 years undergoing non- cardiac surgery 3 groups: Hct 54 30 day mortality increase by 1.6% for every 1% change in Hct<39– Wu et al
Features of unexplained anaemia
Possible causes Age related renal insufficiency pronounced decline in DM/HT Chronic inflammation Stem cell ageing Reduced regenerative capacity Androgen insufficiency Shortened red cell survival
Investigations Blood film Reticulocyte count Ferritin, STR, Haematinics Haemolytic screen Thyroid function Erythropoietin level Bone marrow biopsy
Erythropoietin MW 30400Da Discovered by Miyake et al in 1977 LC 4 alpha helical bundle class 1 cytokine
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
Biology Epo stimulates erythropoiesis Low oxygen supply increases the production of Epo Produced by the interstitial cells in kidney
32 week randomised, double blinded crossover trial with placebo and Epoetin alpha in elderly - Agnihotri P et al 62 patients with chronic anaemia
Increase in Hb>2 g/dl Improvement in QOL studies
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.
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
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.