Drug-induced alterations to B12/folate metabolism (e.g. methotrexate)
Iron deficiency
Reduced EPO (e.g. renal failure)
Chronic inflammatory states
Appropriate sequestration of abnormal RBCs by the RES
Sickle cell anaemia
Thalassaemias
Methaemaglobinaemia
Increased loss
Traumatic haemorrhage
GI loss including acute (e.g. UGIB) and chronic (e.g. coeliac disease)
Surgical loss
Excess sampling (iatrogenic)
Haemolysis; immune, mechanical
DIC
Anaemia of inflammation is highly prevalent in those with chronic disease states, such as:
Cancer (40-80%)
Inflammatory bowel diseases (67%)
CKD (21 - 62%)
Congestive heart failure (30 - 50%)
Chronic pulmonary diseases (8 - 33%)
Auto-immune diseases such as rheumatoid arthritis, lupus
The true prevalence is, however, hard to quantify as it often co-exists with other causes of anaemia
Pathophysiology
Decreased iron availability
Cytokine release secondary to inflammation stimulates synthesis of hepcidin
High hepcidin level promotes 'iron trapping' in macrophages and the bone marrow
Therefore although available iron is low, iron stores are normal and treatment with exogenous iron is often ineffective
Reduced free iron availability impairs erythropoiesis and development of erythroid progenitors
Cytokine-activated macrophages demonstrate an increased rate of erythrocyte phagocytosis, reducing RBC circulating half-life
Cytokines act directly on the bone marrow to reduce the rate of erythropoiesis, independent of circulating EPO levels
Supressed production of EPO, which may be a cytokine-related effect on renal EPO secretion
Clinical features of anaemia are largely non-specific, and reflect inadequate tissue oxygenation ± the cardiovascular adaptations thereof
Clinical features of anaemia
Lethargy
Malaise
Dyspnoea
Palpitations
Dizziness
Insomnia
Confusion
Fatigue
Angina
History and examination
Clinical features including bleeding history
Alcohol history
Drug history
Features of neoplastic process
Family history suggestive of haemoglobinopathy
Bloods
Full blood count for Hb, MCV
Blood film
Folate and B12 levels
Iron studies (see below)
Renal function
Liver function tests
Thyroid function tests
Coagulation studies for DIC or MAHA
Serum electrophoresis (paraprotein in myeloma)
Tests for haemolysis
Direct Coombs test (positive in immune haemolysis)
Conjugated/unconjugated bilirubin
LDH (increased in haemolysis)
Haptoglobin (decreased in haemolysis)
Reticulocyte count (>2% in haemolysis i.e. hyperproliferative state)
Reticulocyte count
<2% in hypoproliferative states e.g. leukaemia, aplastic anaemia and other marrow failure syndromes
>2% in hyperproliferative states e.g. haemolysis, haemorrhage
Iron studies
Ferritin
A sensitive marker but an acute phase protein which may be raised in inflammatory and neoplastic states
A ferritin of <30μg/L is indicative of iron deficiency anaemia
A ferritin of 30-100μg/L combined with a raised CRP (>5mg/L) or in the context of impaired renal function (eGFR <60ml/min) implies IDA + functional iron deficiency
A ferritin >100μg/L may imply functional iron deficiency if there are low transferrin saturations (<20%), but may indicate other causes of anaemia are present
Transferrin saturations
Decreased in iron deficiency
A value <20% is either indicative of IDA (if ferritin is low) or functional iron deficiency (if ferritin is normal)
Soluble transferrin receptor; increased in response to cellular iron deficiency and not affected by inflammation
Iron binding capacity; may be increased (iron deficiency, haemorrhage) or decreased (anaemia of chronic disease, thalassaemia)
Serum iron level; low levels suggest iron deficiency BUT sensitive to dietary iron intake and fluctuates diurnally
Imaging
GI blood loss
Faecal occult blood testing
Endoscopy (upper/lower)
If age ≥60yrs + iron deficiency anaemia needs two week wait referral for possible malignancy
Prevalence of cancer in unexplained IDA is 15%
Tissue oxygen delivery (DO2) is determined by arterial oxygen content (CaO2) and cardiac output (CO)
Arterial oxygen content is in turn predominantly determined by the proportion of haemoglobin bound by oxygen
Indeed, DO2 and haemoglobin concentration scale somewhat linearly (presuming factors such as saturations, PaO2 and cardiac output remain constant):
Hb (g/L)
DO2 (mlO2/min)
150
1000
125
836
100
672
75
508
Anaemia therefore causes tissue hypoxia, leading to activation of a series of compensatory mechanisms in order to restore tissue oxygen supply
Oxygen release and extraction
Increased organ oxygen extraction
Organs such as the kidneys, skeletal muscle and skin increase oxygen extraction ratio
Leads to an overall increase in total body extraction and a decrease in venous oxygen saturations, although the effect may be modest even at extremes of anaemia
Organs with a high oxygen extraction ratio (myocardium, brain) are unable to compensate using this mechanism
Shifting oxyhaemoglobin dissociation curve
Increase 2,3-DPG and hydrogen ions
Reduces affinity of haemoglobin for oxygen
Shifts dissociation curve to the right
Favours oxygen release to the tissues at a higher partial pressure of oxygen than before
Cardiovascular adaptations
With CaO2 somewhat kiboshed by the low haemoglobin levels, the cardiovascular system bears the brunt of trying to restore DO2
Aortic arch chemoreceptors are triggered by hypoxia (low DO2) rather than the change in haemoglobin levels per se
Afferent signal via vagus nerve to nucleus tractus solitarius
Efferent effects via decreased vagal activity (and to a degree sympathetic activation), causing
Tachycardia
Increased stroke volume
Increased cardiac output/cardiac index
The increase in cardiac index with increasing anaemia is exponential although the gradient is steepens below an Hb of 70g/L
Redistribution of cardiac output to increase flow to organs with high oxygen demand (brain, myocardium)
Reduced systemic vascular resistance
Mostly due to locally-mediated nitric oxide pathways are activated by reduced tissue DO2 as part of the normal autoregulatory mechanisms for regional blood flow
A small element of the reduced SVR is due to decreased blood viscosity (as per the Hagen-Poiseuille equation)
Not thought to be an autonomic phenomenon
Maintained CVP/PCWP unless haemorrhage is cause of blood loss
Intracellular adaptations
Cellular hypoxia triggers release of the aptly named Hypoxia-inducible factor 1 (HIF-1)
HIF-1 in turn triggers transcription of hypoxia-response genes such as:
Erythropoietin
Vascular endothelium growth factor (VEGF)
Various genes involved in switching intracellular metabolism to be better suited to anaerobic utilisation of glucose
Chronic adaptations
Eventually in chronic anaemia there is activation of neurohumoral mechanisms involved in regulating blood pressure, even if euvolaemic
High levels of serum catecholamines
RAAS-mediated salt retention
Vasopressin- and aldosterone-mediated body water volume expansion