title: Clinical and laboratory significance of defective P2Y(12) pathway function in patients with myeloproliferative neoplasms: a pilot study.
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.
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taiwan, China.
authors.forename: Hung
authors.initials: H
authors.lastname: Chang
authors.forename: Lee-Yung
authors.initials: LY
authors.lastname: Shih
authors.forename: Alan D
authors.initials: AD
authors.lastname: Michelson
authors.forename: Po
authors.initials: P
authors.lastname: Dunn
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Frelinger
authors.forename: Po-Nan
authors.initials: PN
authors.lastname: Wang
authors.forename: Ming-Chung
authors.initials: MC
authors.lastname: Kuo
authors.forename: Tung-Liang
authors.initials: TL
authors.lastname: Lin
authors.forename: Jin-Hou
authors.initials: JH
authors.lastname: Wu
authors.forename: Tzung-Chih
authors.initials: TC
authors.lastname: Tang
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D005260:Female; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism*; D006470:Hemorrhage / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D007958:Leukocyte Count; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D010865:Pilot Projects; D010979:Platelet Function Tests; D016133:Polymerase Chain Reaction; D058472:Receptors, Purinergic P2Y1 / Q000235:genetics / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics / Q000378:metabolism*; D013927:Thrombosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; C548576:P2RY12 protein, human; D010750:Phosphoproteins; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D000098662:Vasodilator-Stimulated Phosphoprotein; C507924:JAK2 protein, human; D053614:Janus Kinase 2