Clinical and laboratory significance of defective P2Y(12) pathway function in patients with myeloproliferative neoplasms: a pilot study

Acta Haematol. 2013;130(3):181-7. doi: 10.1159/000348413. Epub 2013 Jun 8.

Abstract

Background: Patients with myeloproliferative neoplasms (MPN) have an increased risk for thrombosis and bleeding and show a defect in adenosine diphosphate (ADP)-induced platelet aggregation. This risk of thrombosis is further increased in MPN patients bearing the JAK2V617F mutation. Two ADP receptors, P2Y1 and P2Y12, are present on platelets. Although the pattern of defective ADP-induced platelet aggregation in MPN suggests an abnormality in the P2Y12 pathway, no previous studies have specifically evaluated P2Y12 function in MPN or the relationship between P2Y12 function and the JAK2V617F mutation.

Methods: Forty-one MPN patients were enrolled, including 24 with essential thrombocythemia (ET), 16 with polycythemia vera (PV) and 1 with primary myelofibrosis. Platelet P2Y12 function in MPN was evaluated by flow-cytometric measurement of the phosphorylation of vasodilator-stimulated phosphoprotein (VASP). Clinical data were collected by review of medical records. JAK2V617F mutation was detected by allele-specific polymerase chain reaction. JAK2V617F allele burden was measured by the pyrosequencing method.

Results: In patients with MPN, platelet P2Y12 function determined by VASP platelet reactivity index (PRI) was inversely correlated with platelet and white blood cell (WBC) counts. In subgroup analysis, PRI was inversely correlated with platelet and WBC counts in PV. PRI was also inversely correlated with platelet counts in ET, but the correlation of PRI and WBC counts did not reach statistical significance. Eight of the 41 patients had a history of thrombosis and only 2 had a bleeding history. Neither thrombosis nor bleeding patients were found to have significantly different PRIs. JAK2V617F mutation data were available in 35 cases. PRI was not different between JAK2V617F mutation and wild-type patients but PRI had a trend towards an inverse correlation with JAK2V617F allele burden for patients with mutations.

Conclusions: The present study provides the first explicit demonstration of a defect in the P2Y12 pathway in platelets of patients with MPN. Furthermore, platelet P2Y12 function, assayed by VASP, is inversely correlated with platelet and WBC counts in patients with MPN. Platelet P2Y12 function also appears to be inversely correlated with JAK2V617F allele burden. This compromised P2Y12 function may be a novel mechanism for the bleeding tendency associated with extreme thrombocytosis in MPN.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Substitution
  • Blood Platelets / metabolism*
  • Blood Platelets / pathology
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Female
  • Hematologic Neoplasms / genetics
  • Hematologic Neoplasms / metabolism*
  • Hemorrhage / etiology
  • Hemorrhage / genetics
  • Hemorrhage / metabolism
  • Hemorrhage / pathology
  • Humans
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Leukocyte Count
  • Male
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Middle Aged
  • Mutation, Missense
  • Myeloproliferative Disorders / genetics
  • Myeloproliferative Disorders / metabolism*
  • Myeloproliferative Disorders / pathology
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation / genetics
  • Pilot Projects
  • Platelet Function Tests
  • Polymerase Chain Reaction
  • Receptors, Purinergic P2Y1 / genetics
  • Receptors, Purinergic P2Y1 / metabolism
  • Receptors, Purinergic P2Y12 / genetics
  • Receptors, Purinergic P2Y12 / metabolism*
  • Thrombosis / etiology
  • Thrombosis / genetics
  • Thrombosis / metabolism
  • Thrombosis / pathology

Substances

  • Cell Adhesion Molecules
  • Microfilament Proteins
  • Neoplasm Proteins
  • P2RY12 protein, human
  • Phosphoproteins
  • Receptors, Purinergic P2Y1
  • Receptors, Purinergic P2Y12
  • vasodilator-stimulated phosphoprotein
  • JAK2 protein, human
  • Janus Kinase 2