Lecture 10 - Introduction to Haematological Disorders - Polycythaemia/Erythrocytosis Flashcards
General Concepts - Polycythaemia/Erythrocytosis
Increased RBC mass
Archaic ‘plethora’
Greater than upper limit of an appropriate reference interval
Erythrocytosis = increased RBC concentration
Polycythaemia = increased RBC mass (Hb, Hct, RBC)
Blood Volume
Blood volume is composed of red cell volume (RCV) and plasma volume (PV)
These can be determined by dilution analysis
- a small volume of identifiable radioisotope is injected intravenously either bound to red cells or a component of plasma
- amount of dilution is measured after time to allow mixing in circulation
RCV can be determined with 51Cr label aliquot of patient RBC
PV can be determined with 125I-labelled albumin
Absolute polycythaemia RCV > 25% predicted volume
Clinical Signs of Polycythemia
Typically non-specific
- e.g. fatigue, dizziness, headache
Many cases are asymptomatic
- detected by FBC
Investigation warranted if Hct > 0.54 L/L (male) and > 0.48 L/L (female) persisting for > 2 months
If Hct > 0.60 L/L (male) and > 0.56 L/L (female) then mostly absolute polycythaemia
Clinical Consequences of Erythrocytosis
Excessive haematocrit has rheological consequences
- decreased blood flow
- decreased oxygen delivery
Prolonged excessive production of RBC may progress to bone marrow exhaustion, fibrosis and anaemia
Relative Polycythaemia/Erythrocytosis
Results from decreased plasma volume Commonly due to dehydration - loss of plasma volume relative to RBC volume - typically transient - history of inadequate water - resolves when adequately hydrated Also occurs with edema, diuretic drugs, prolonged bed rest, smoking E.g Gaisbock Syndrome
Gaisbock Syndrome
Relative polycythaemia
Decreased plasma volume
Normal RBC mass
Typically occurs in obese, hypertensive, middle-aged, males
Absolute Polycythaemia/Erythrocytosis
Results from increased red cell volume (red cell mass) Normal plasma volume May be either primary or secondary Primary - autonomous production of RBC Secondary - stimulated production of RBC
Primary Absolute Erythrocytosis
Autonomous production of mature RBC
Essentially RBC neoplasia
Typically results from well differentiated neoplasia -> ‘mature’ RBC released into the peripheral blood
No hypoxic stimulus responsible for production of cells
Bone marrow shows increased production of RBC
- decreased myeloid:erythroid ratio in bone marrow
Orderly maturation sequence
Essentially too much production of ‘normal’ RBC
Polycythaemia Vera
Neoplastic production of well differentiated RBC named ‘Polycythaemia vera’
Myeloproliferative disorder
Typically results in increased Hb, RBC, Hct values
Thrombocytosis may also be apparent
Usually occurs in middle aged and older adults
Typically has a slowly progressive course
Eventually results in fibrosis of the bone marrow and failure to produce RBC
Most cases (>95%) of polycythaemia vera have a mutation in the Janus kinase 2 gene (JAK2 V617F)
Secondary Absolute Erythrocytosis
Increased erythropoiesis in response to stimulus Increased RCV/RCM due to increased production of RBC Typically mediated via erythropoietin (Epo) Several mechanisms - general hypoxia - local hypoxia - exogenous Epo - epo receptor interactions - oxygen sensing mechanisms May be: - congenital - acquired
Therapy Induced Erythrocytosis
A range of substances used therapeutically can modify erythropoiesis
Human recombinant erythropoietin is commonly used therapeutically to stimulate erythropoiesis in patients with anaemia
- e.g. post cytotoxic chemotherapy and bone marrow transplant to promote RBC production
- e.g. in cases of chronic renal failure to promote RBC production
Testosterone is used to treat a range of endocrine disorders including hypogonadism
- testosterone has a range of anabolic effects and increases erythropoiesis
Secondary Absolute Erythrocytosis Mechanism - Central Hypoxia
Mechanism:
- central ‘widespread’ hypoxia
- -> tissue hypoxia -> increased Epo production (kidney, liver)
- -> Epo mediated increased erythropoiesis -> increased RCM
Many potential causes:
- high altitude
- chronic lung disease
- right-to-left cardiopulmonary vascular shunts
- carbon monoxide poisoning
- smoker’s erythrocytosis
- hypoventilation syndromes including sleep apnoea
Secondary Absolute Erythrocytosis - Renal Hypoxia
Epo is predominantly produced in the kidney
Mechanism:
- local renal hypoxia
- =>renal tissue hypoxia => ↑ Epo production (kidney)
- => Epo mediated ↑ erythropoiesis => ↑ RCM
Causes include:
- renal artery stenosis
- end-stage renal disease
- hydronephrosis
- renal cysts (polycystic kidney disease)
- post-renal transplant erythrocytosis
Secondary Absolute Erythrocytosis Mechanism - Pathologic Epo Production
Results from pathologic production of Epo by neoplastic cells
Mechanism:
- ↑ Epo production by neoplastic cells (not related to hypoxia)
- => Epo mediated ↑ erythropoiesis => ↑ RCM
Tumours (many):
- cerebellar hemangioblastoma
- meningioma
- parathyroid carcinoma/adenomas
- hepatocellular carcinoma
- renal cell cancer
Hereditary Erythrocytosis
Number of very rare inherited syndromes may result in increased RCV/RCM
Most common (of these rare disorders) due to mutation in Epo receptors
- gain of function phenotype
- increased sensitivity of RBC precursor stages of Epo
- => increased RBC production
