Differentials
Secondary polycythaemia owing to hypoxia
SIGNS / SYMPTOMS
History and examination suggest an underlying cause of hypoxia.
Possible causes include smoking or lung disease.
Sleep apnoea in association with an underlying lung disease may be a possible cause.
INVESTIGATIONS
Erythropoietin level is normal or elevated with secondary polycythaemia.
Oxygen saturation on room air <92% suggests significant hypoxia.
Arterial blood gas confirms the result.
Overnight oximetry can be abnormal in people with sleep apnoea. However, obstructive sleep apnoea, as an isolated factor, is unlikely to produce erythrocytosis. Therefore, presence of an underlying lung disease should be investigated.
Pulmonary function tests (spirometry and diffusing capacity of the lung for carbon monoxide) are abnormal in people with underlying lung disease.
Essential thrombocythaemia (ET)
SIGNS / SYMPTOMS
May be clinically indistinguishable, although patients with ET do not have aquagenic pruritus (itching after contact with warm water) and plethora.
INVESTIGATIONS
Isolated thrombocytosis with normal erythropoietin, haemoglobin, red cell mass, haematocrit, and plasma volume suggests ET.
A positive calreticulin (CALR) or thrombopoietin receptor (MPL) mutation generally excludes PV, and suggests a diagnosis of ET or primary myelofibrosis.[85][86][87][88] However, there have been reports of CALR mutations in patients with PV.[89]
Usually no history of elevated haemoglobin, but 3% to 5% of patients with ET may have haemoglobin levels indicative of PV.[81] However, 20% to 30% of these cases do not have JAK2 mutations, and all appear to have bone marrow features characteristic of ET.[97]
Primary myelofibrosis
SIGNS / SYMPTOMS
Evidence of hepatomegaly and extramedullary haematopoiesis suggests primary myelofibrosis.
INVESTIGATIONS
Bone marrow fibrosis with normal erythropoietin, haemoglobin, red cell mass, haematocrit, and plasma volume suggests primary myelofibrosis.
Absence of leukoerythroblastosis on peripheral blood smear.
A positive CALR or MPL mutation generally excludes PV, and suggests a diagnosis of essential thrombocythaemia or primary myelofibrosis.[85][86][87][88] However, there have been reports of CALR mutations in patients with PV.[89]
Imaging studies may reveal extramedullary haematopoiesis.
Chronic myeloid leukaemia (CML)
SIGNS / SYMPTOMS
May be clinically indistinguishable, although thrombosis is much less common with CML.
INVESTIGATIONS
Fluorescence in situ hybridisation (FISH) or polymerase chain reaction (PCR) positive for Philadelphia chromosome (BCR::ABL1 fusion gene).
Polycythaemia owing to elevated erythropoietin level
SIGNS / SYMPTOMS
There may be evidence of the presence of an erythropoietin-secreting tumour.
There may be a family history of familial polycythaemias such as Chuvash polycythaemia.
Patient may be receiving exogenous erythropoietin.
INVESTIGATIONS
Elevated erythropoietin level.
Imaging studies may reveal an erythropoietin-secreting tumour.
Polycythaemia owing to anabolic steroid or testosterone use
SIGNS / SYMPTOMS
History of anabolic steroid or exogenous testosterone supplementation.
INVESTIGATIONS
No other differentiating tests required following appropriate history.
If there is no clear history that erythrocytosis began with the initiation of anabolic steroid or testosterone, a trial cessation can be used to confirm; haemoglobin should return to normal.
Congenital polycythaemia
SIGNS / SYMPTOMS
Appropriate family history can be helpful but is not always revealing.
Autosomal dominant history suggests activating erythropoietin receptor mutation, gain of function mutation of HIF2 alpha gene, or high-affinity haemoglobin.
Recessive history suggests Chuvash polycythaemia.
INVESTIGATIONS
Specialised genetic tests will be positive for the particular congenital disorder present.
P50 measurement (the oxygen tension corresponding to 50% oxygen saturation) gives a quantitative measure of haemoglobin oxygen affinity. Increased oxygen affinity of haemoglobin, reflected in a low P50, left-shifted oxygen dissociation curve, and loss of normal sigmoidal configuration, is characteristic of many haemoglobin variants that can be responsible for polycythaemia. The same may occur with 2,3-BPG deficiency, congenital methaemoglobinaemia, or mutations in the hypoxia signalling pathway (e.g., loss of function mutations in VHL or PHD2, or gain of function HIF-2alfa mutations).[13]
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