The Association of Leukocytosis, Thrombocytosis and JAK2V617F Mutation with Thrombotic Events in Myeloproliferative Disorders (MPD’s)

Abstract

Background: Essential thrombocythemia (ET) and Polycythemia vera (PV) are clonal diseases, present at diverse ends in the spectrum of MPD’s. Recently, there has been an increased interest in the association of leukocytosis, thrombocytosis and the presence of JAK2V617F mutation with the risk of thrombosis in patients with ET. Although, leukocytosis and the presence of JAK2V617F mutation has been proposed as prognostic indicators for thrombosis, the correlation of thrombocytosis with thrombotic risk remains unclear. In the current study, we examined the association of the predictors of thrombosis – leucocytosis, thrombocytosis and JAK2V617F mutation, in patients with both ET and PV in a community hospital cohort. Methods: We conducted a retrospective review of all patients with ET and PV receiving treatment at the Cleveland Clinic Cancer Center at Fairview Hospital between January 2001 and December 2007. Data on risk factors (leucocytosis, thrombocytosis and JAK2V617F mutation status) at diagnosis were collected. Pearson Chi-square test was used to analyze the association between the above-mentioned variables and thrombosis (both arterial and venous). In addition to analyzing the entire cohort, separate subgroup analyses were also performed on the individual groups (patients with PV and those with ET). All analyses were performed using SAS software (Cary, NC). Results: One-hundred and eight patients were identified. The median age was 67 years (range 28–89), and 57 patients (53%) were female. WBC counts and platelet counts were found to be positively associated with the presence of thrombosis (p<0.001). The proportion of patients with thrombosis for the group with leukocyte count >=10,000 were significantly higher than that for the group with WBC counts <10,000 (76.9% vs. 18.6%, p<0.001). The proportion of patients with thrombosis for the group with platelet count >=400,000 were significantly higher than that for the group with platelet counts <400,000(60.0% vs. 35.7%, p=0.027). There was also a significant association between the presence of JAK2V617F mutation and thrombosis (p<0.001). [Table 1]. Table 1: Association of risk factors and thrombotic events among patients with MPD. THROMBOSIS Yes No RISK FACTORS Level Total N (%) N (%) P value Leukocyte Count . . . . . <0.001 <10,000/mm3 43 8 18.6 35 81.4 >=10,000/mm3 65 50 76.9 15 23.1 Platelet Count . . . . . 0.027 <400,000/ml 28 10 35.7 18 64.3 >=400,000/ml 80 48 60 32 40 JAK2V617F mutation . . . . . <0.001 NEG 34 5 14.7 29 85.3 POS 44 38 86.4 6 13.6 Not Performed 30 15 50 15 50 Among the cohort with ET (N=59) leucocytosis was significantly associated with thrombosis. The proportion of patients with thrombosis for the group with WBC counts >=10,000 were significantly higher than that for the group with counts <10,000 (81.8% vs. 11.5%, p<0.001). Also, the presence of the JAK2V617F mutation was significantly associated with thrombosis (87% vs.11.8%, p=<001). Among the cohort with PV (N=49), leucocytosis was significantly associated with the presence of thrombosis. The proportion of patients with thrombosis for the group with WBC counts >=10,000 were significantly higher than that for the group with a count <10,000 (71.9% vs. 29.4%, p<0.004). Significant association (p<0.001) was observed between the presence of JAK2V617F mutation and thrombosis (85.7% vs. 17.7, p=<001). Conclusion: Leucocytosis, thrombocytosis and the presence of JAK2V617F mutation are significant risk factors for thrombotic events among patients with MPD. Additionally, while in both subgroups (patients with PV and ET) leucocytosis and the presence of the JAK2V617F mutation were significant risk factors for thrombosis, thrombocytosis was not found to be significantly associated with presence of thrombosis. Even though the results of this retrospective analysis deserve to be confirmed by prospective studies, it strengthens the view that in the treatment of MPD’s (specifically ET), panmyelosuppression would be more efficacious than targeting platelets alone as a modality of therapy for MPD.

A distinct molecular mutational profile and its clinical impact in essential thrombocythemia and primary myelofibrosis patients

“…It is suggested that this mutation likely causes thrombosis through multiple mechanisms, including activation of platelets and granulocytes [39,40]. More recently, the association of leucocytosis and JAK2 mutation with thrombotic events has been confirmed in a retrospective study of 108 patients with ET [41]. Increased rate of vascular complications in ET have been associated with two variables, age and previous thrombotic history [42].…”