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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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  • Pathogenesis and management of essential thrombocythemia
  • Idiopathic erythrocytosis: a disappearing entity
  • Therapeutic potential of JAK2 inhibitors
  • Relationship of ET to PV and PMF

The level of JAK2-STAT5 signaling provides a rheostat that determines whether the disease phenotype is predominantly erythroid or megakaryocytic.

Several lines of evidence suggest a blurring of the distinction between these disorders. A proporation of patients diagnosed with ET (see Table 1 for criteria) harbor increased levels of bone marrow reticulin in the absence of other features suggesting a diagnosis of PMF
The variable degree of reticulin accumulation reflects the combined effects of genetic background, disease duration, therapy, clonal burden and the acquisition of additional genetic lesions.
table 1 suggested diagnostic criteria for essential thrombocythemia et
Table 1.Suggested diagnostic criteria for essential thrombocythemia(ET)

Diagnosis requires A1-A3 OR A1+A3-A5

  • A1 Sustained platelet count >450X109/L.
  • A2 Presence of an acquired pathogenetic mutation(eg, in JAK2 or MPL).
  • A3 No other myeloid malignancy, especially polycythemia vera(PV), primary myelofibrosis(PMF), chronic myeloid leukemia(CML) or myelodysplastic syndrome(MDS).
  • A4 No reactive cause for thrombocytosis and normal iron stores.
  • A5 Bone marrow trephine histology showing increased megakaryocytes with prominent large hyperlobated forms; reticulin is generally not increased(≤2 on a 0-4 scale).
Familial Predisposition to ET and Other Myeloproliferative Neoplasms

A relative risk of 7.4 for developing ET in those with an affected first-degree relative.

Are Mutations in JAK2 Disease-initiating Events?

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

Progression to acute myeloid leukemia(AML) occurs in a small minority of ET patients and involves the accrual of further genetic events.

Diagnosis and Management

Diagnostic Criteria

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.

  • Low-dose aspirin
  • Cytoreductive therapy
  • Hydroxyurea
  • Anagrelide
  • JAK2 inhibitors
Classification of Erythrocytoses

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).

table 2 causes of an erythrocytosis
Table 2.Causes of an erythrocytosis
  • Primary Erythrocytosis
  • Secondary erythrocytosis
  • Idiopathic erythrocytosis
table 2 causes of an erythrocytosis1
Table 2.Causes of an erythrocytosis
  • Primary Erythrocytosis


Erythropoietin(EPO) receptor mutations


Polycythemia vera (including JAK2 exon 12 mutations)

Secondary erythrocytosis


Defects of the oxygen sensing pathway

VHL gene mutation (Chuvash erythrocytosis)

PHD2 mutations

HIF-2a mutations

Other congenital defects

High oxygen-affinity hemoglobin

Bisphosphoglycerate mutase deficiency



Central hypoxia

Chronic lung disease

Right-to-left cardiopulmonary vascular shunts

Carbon monoxide poisoning

Smoker′s erythrocytosis

Hypoventilation syndromes including obstru-

ctive sleep apnea


Local hypoxia

Renal artery stenosis

End-stage renal disease


Renal cysts (polycystic kidney disease)

Post-renal transplant erythrocytosis

Pathologic EPO production


Cerebellar hemangioblastoma


Parathyriod carcinoma/adenomas

Hepatocellular carcinoma

Renal cell cancer


Uterine leiomyomas

Drug associated

Erythropoietin administration

Androgen administration

Investigation of an Erythrocytosis

Once an erythrocytosis has been established identification of the cause is the next focus.

  • Clinical Consequences

A raised red cell count will increase the viscosity and thus may have clinical consequences.

  • Management of an Erythrocytosis

Reducing the Hct by phlebotomy/venesection reduces the blood viscosity and maybe of benefit.

  • Cytoreductive
  • Low-dose aspirin
The V617F mutation is localized in a region outside the adenosine triphosphate(ATP)-binding pocket of JAK2 enzyme, ATP-competitive inhibitors of JAK2 kinase are not likely to discriminate between wild-type and mutant JAK2 enzymes. Therefore, JAK2 inhibitors, by virtue of their near equipotent activity against wild-type JAK2 that is important for normal hematopoiesis, may have adverse myelosuppression as an expected side effect, if administered at doses that aim to completely inhibit the mutant JAK2 enzyme.
While they may prove to be effective in controlling hyperproliferation of hematopoietic cells in PV and ET, they may not be able to eliminate mutant clones.

Most importantly, patients with and without the JAK2 V617F mutation appear to benefit to the same extent.