Differentials
Secondary polycythemia owing to hypoxia
SIGNS / SYMPTOMS
History and exam suggest an underlying cause of hypoxia.
Possible causes include smoking or lung disease.
Sleep apnea in association with an underlying lung disease may be a possible cause.
INVESTIGATIONS
Erythropoietin level is normal or elevated with secondary polycythemia.
Oxygen saturation on room air <92% suggests significant hypoxia.
Arterial blood gas confirms the result.
Overnight oximetry can be abnormal in people with sleep apnea. However, obstructive sleep apnea, 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 thrombocythemia (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, hemoglobin, red cell mass, hematocrit, 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.[84][85][86][87] However, there have been reports of CALR mutations in patients with PV.[88]
Usually no history of elevated hemoglobin, but 3% to 5% of patients with ET may have hemoglobin levels indicative of PV.[80] However, 20% to 30% of these cases do not have JAK2 mutations, and all appear to have bone marrow features characteristic of ET.[96]
Primary myelofibrosis
SIGNS / SYMPTOMS
Evidence of hepatomegaly and extramedullary hematopoiesis suggests primary myelofibrosis.
INVESTIGATIONS
Bone marrow fibrosis with normal erythropoietin, hemoglobin, red cell mass, hematocrit, 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 thrombocythemia or primary myelofibrosis.[84][85][86][87] However, there have been reports of CALR mutations in patients with PV.[88]
Imaging studies may reveal extramedullary hematopoiesis.
Chronic myeloid leukemia (CML)
SIGNS / SYMPTOMS
May be clinically indistinguishable, although thrombosis is much less common with CML.
INVESTIGATIONS
Fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) positive for Philadelphia chromosome (BCR::ABL1 fusion gene).
Polycythemia owing to elevated erythropoietin level
SIGNS / SYMPTOMS
There may be evidence of the presence of an erythropoietin-secreting tumor.
There may be a family history of familial polycythemias such as Chuvash polycythemia.
Patient may be receiving exogenous erythropoietin.
INVESTIGATIONS
Elevated erythropoietin level.
Imaging studies may reveal an erythropoietin-secreting tumor.
Polycythemia 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; hemoglobin should return to normal.
Congenital polycythemia
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 hemoglobin.
Recessive history suggests Chuvash polycythemia.
INVESTIGATIONS
Specialized 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 hemoglobin oxygen affinity. Increased oxygen affinity of hemoglobin, reflected in a low P50, left-shifted oxygen dissociation curve and loss of normal sigmoidal configuration, is characteristic of many hemoglobin variants that can be responsible for polycythemia. The same may occur with 2,3-BPG deficiency, congenital methemoglobinemia, or mutations in the hypoxia signaling pathway (e.g., loss of function mutations in VHL or PHD2, or gain of function HIF-2alfa mutations).[13]
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