Myeloproliferative Disorders. HongzhiXu Shandong Provincial Hospital. CONTENTS. Pathogenesis and management of essential thrombocythemia Idiopathic erythrocytosis: a disappearing entity Therapeutic potential of JAK2 inhibitors.
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The level of JAK2-STAT5 signaling provides a rheostat that determines whether the disease phenotype is predominantly erythroid or megakaryocytic.
Diagnosis requires A1-A3 OR A1+A3-A5
A relative risk of 7.4 for developing ET in those with an affected first-degree relative.
The acquisition of a JAK2 mutation was preceded by either a deletion of chromosome 20q24 or a mutation in TET2.
Direct evidence now exists demonstrating that JAK2 mutations are not the disease-initiating event in some patients, although the frequency of this scenario remains unclear.
Progression to acute myeloid leukemia(AML) occurs in a small minority of ET patients and involves the accrual of further genetic events.
Mutations in JAK2 exon 12 are not thought to occur in patients with ET.
The combination of an isolated thrombocytosis with a pathogenetic mutation, in the absence of iron deficiency or features of PMF, is usually sufficient to make a diagnosis of ET.
An erythrocytosis can be classified depending on the identified cause. The main division is on the basis of primary causes, where an intrinsic defect in the erythroid progenitor cell is associated with an enhanced response to cytokines; or secondary, where the increased red cell production is driven by factors external to the erythroid compartment, such as increased erythropoietin(EPO) production for any reason. Primary and secondary causes can be classified further as either congenital or acquired(Table2).
Erythropoietin(EPO) receptor mutations
Polycythemia vera (including JAK2 exon 12 mutations)
Defects of the oxygen sensing pathway
VHL gene mutation (Chuvash erythrocytosis)
Other congenital defects
High oxygen-affinity hemoglobin
Bisphosphoglycerate mutase deficiency
Chronic lung disease
Right-to-left cardiopulmonary vascular shunts
Carbon monoxide poisoning
Hypoventilation syndromes including obstru-
ctive sleep apnea
Renal artery stenosis
End-stage renal disease
Renal cysts (polycystic kidney disease)
Post-renal transplant erythrocytosis
Renal cell cancer
Once an erythrocytosis has been established identification of the cause is the next focus.
A raised red cell count will increase the viscosity and thus may have clinical consequences.
Reducing the Hct by phlebotomy/venesection reduces the blood viscosity and maybe of benefit.
Most importantly, patients with and without the JAK2 V617F mutation appear to benefit to the same extent.