Unexplained AnaemiaAcute Medicine Update

Dr.Srinivasan NarayananConsultant in HaematologyUniversity Hospital Southampton NHSFT

Introduction

Common causes Rare causes Unexplained causes

?Pathophysiology Investigations Treatment options

Summary

Common causes of Anaemia

Diagnosis

Diagnosis

Diagnosis

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

MDS

MDS

Rare causes

Inherited Haemoglobinopathy disorders

eg.unstable Hb Enzyme and membrane disorders Congenital dyserythropoietic anaemias Sideroblastic anaemias

Acquired Aplastic anaemia Paroxysmal nocturnal haemoglobinuria

Diagnosis?

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

Ring sideroblasts

Ring sideroblasts

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

CDA-II

Diagnosis

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

Transmembraneprotein

CD55 CD59

GPI anchors

PNH Hemolytic screen Flow cytometry Bone marrow biopsy Treatment:

Anticoagulation Eculizumab – monoclonal antibody against

C5 Bone marrow transplantation

Unexplained anaemia Commonly mild anaemia (1-2 g/dl

low)

Normocytic

Usually multifactorial

Is it common?

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

Is it clinically relevant?

Retrospective cohort study of over 300000 patients 1997-2004

Age over 65 years undergoing non-cardiac surgery

3 groups: Hct<39, 39-53.9, >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 100-120g/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.

Any Questions?