title: Is the absence of JAK2 mutation a risk factor for bleeding in essential thrombocythemia? An analysis of 106 patients.
abstract: BACKGROUND
  JAK2(V617F) mutation has been recognized as a possible thrombotic risk factor in essential thrombocythaemia (ET). It's role is probably due to an increased myeloid proliferation and white blood cells (WBC) activation. Only few data are available about the effect of JAK2(V617F) on hemorrhagic risk. The aim of our study was to evaluate the influence of the mutational status on hemorrhagic complication.
  
  
  METHODS
  We retrospectively analysed laboratory and clinical findings of 106 consecutive patients with ET to evaluate possible relationships between thrombosis, abnormal bleeding, peripheral blood count, overexpression of PRV1 and JAK2(V617F) mutational status.
  
  
  RESULTS
  ON UNIVARIATE ANALYSIS WE FOUND: an association between JAK2(V617F) mutation and thrombotic events before or at diagnosis (p<0.003, OR=4.44, 95% CI=1.74-12.4); no statistical correlation between the median value of JAK2(V617F) burden and an increased risk of thrombosis (p=0.4, 95% CI= -22.8-10.4); significant relationships between mutated status and higher haematocrit, high WBC count and low platelet count; and a strong correlation between JAK2(V617F) and PRV1 overexpression (p<0.0001). Moreover, the presence of the JAK2(V617F) mutation and a WBC count greater than 8.4 x 10(9)/L were found to be independent factors related to thrombotic complications in multivariable analysis (p<0.006, OR=3.85, 95% CI=1.3-11.9; and p<0.002, OR=2.8, 95% CI=1.08-7.03, respectively). The prognostic impact of JAK2 mutation status and WBC count on thrombosis was evaluated in the whole cohort. Only new cases occurring in patients without previous thrombotic events were recorded for the analysis. The multivariable analysis showed a statistical correlation between the presence of the mutation and a WBC count greater than 8.12 x 10(6)/L and an increased risk of thrombosis if no cytoreductive treatment was started at diagnosis (JAK2(V617F) p=0.02; WBC p=0.02; OR=4.97; 95% CI=1.04-23.8). Finally, wild-type JAK2 was associated with a higher haemorrhagic risk (p=0.02) in univariate analysis but only a platelet count greater than 1,022 x 10(9)/L was associated with an increased risk of bleeding in the multivariable analysis.
  
  
  CONCLUSIONS
  Our data confirm the role of both JAK2(V617F) as factor associated with an increased risk of thrombosis at the diagnosis and during follow-up in no treated patients. Moreover a WBC count over 8.4 x 10(9)/L1 was also strictly associated to an increased risk of thrombosis. Regarding bleedings, our statistical analysis allows to exclude the mutation protective role on haemorrhage.
authors.affiliation: Dipartimento di Ematologia, Servizio di Prevenzione e Cura Sindromi Emorragiche e Trombotiche, Ospedale Civile dello Spirito Santo, Pescara, Italy. andreapatriarca80@gmail.com
authors.forename: Andrea
authors.initials: A
authors.lastname: Patriarca
authors.forename: Franca
authors.initials: F
authors.lastname: Pompetti
authors.forename: Raniero
authors.initials: R
authors.lastname: Malizia
authors.forename: Ornella
authors.initials: O
authors.lastname: Iuliani
authors.forename: Ilaria
authors.initials: I
authors.lastname: Di Marzio
authors.forename: Antonio
authors.initials: A
authors.lastname: Spadano
authors.forename: Alfredo
authors.initials: A
authors.lastname: Dragani
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D005260:Female; D058851:GPI-Linked Proteins; D006470:Hemorrhage / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D006801:Humans; D007519:Isoantigens / Q000097:blood / Q000235:genetics; D053614:Janus Kinase 2 / Q000097:blood / Q000235:genetics*; D007958:Leukocyte Count; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D020125:Mutation, Missense; D011956:Receptors, Cell Surface / Q000097:blood / Q000235:genetics; D012189:Retrospective Studies; D012307:Risk Factors; D013920:Thrombocythemia, Essential / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D013927:Thrombosis / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000235:genetics
chemical_list: C407242:CD177 protein, human; D058851:GPI-Linked Proteins; D007519:Isoantigens; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C507924:JAK2 protein, human; D053614:Janus Kinase 2