JAK2V617F variant allele frequency >50% identifies patients with polycythemia vera at high risk for venous thrombosis

Abstract

Arterial (AT) and venous (VT) thrombotic events are the most common complications in patients with polycythemia vera (PV) and are the leading causes of morbidity and mortality. In this regard, the impact of JAK2V617F variant allele frequency (VAF) is still debated. The purpose of the current study was to analyze the impact of JAK2V617F VAF in the context of other established risk factors for thrombosis in a total of 865 2016 WHO-defined PV patients utilizing two independent cohorts: University of Florence (n = 576) as a training cohort and Policlinico Gemelli, Catholic University, Rome (n = 289) as a validation cohort. In the training cohort VT free-survival was significantly shorter in the presence of a JAK2V617F VAF > 50% (HR 4; p < 0.0001), whereas no difference was found for AT (HR 0.9; p = 0.8). Multivariable analysis identified JAK2V617F VAF > 50% (HR 3.8, p = 0.001) and previous VT (HR 2.2; p = 0.04) as independent risk factors for future VT whereas diabetes (HR 2.4; p = 0.02), hyperlipidemia (HR 2.3; p = 0.01) and previous AT (HR 2; p = 0.04) were independent risk factors for future AT. Similarly, JAK2V617F VAF > 50% (HR 2.4; p = 0.01) and previous VT (HR 2.8; p = 0.005) were confirmed as independent predictors of future VT in the validation cohort. Impact of JAK2V617F VAF > 50% on VT was particularly significant in conventional low-risk patients, both in Florence (HR 10.6, p = 0.005) and Rome cohort (HR 4; p = 0.02). In conclusion, we identified JAK2V617F VAF > 50% as an independent strong predictor of VT, supporting that AT and VT are different entities which might require distinct management.

Neutrophil-to-lymphocyte ratio is a novel predictor of venous thrombosis in polycythemia vera

“…It will be interesting to investigate the relationship between NLR values and the allelic burden of JAK2 V617F, which has recently been reported to be correlated with venous thrombosis [ 24 ]. Furthermore, it is worth noting that the association of absolute values of circulating neutrophil, lymphocyte, and monocyte with venous but not with arterial thrombosis was also found in essential thrombocythemia, further corroborating the role of inflammation in thrombogenesis of MPN.…”

Cardiovascular Disease in Myeloproliferative Neoplasms

“… 20 , 21 , 22 Additionally, in polycythemia vera (in which JAK2 mutation accounts for >95% of driver mutations), increased JAK2 V617F burden of mutant leukocytes in peripheral blood (the variant allele frequency) is associated with increased venous thrombosis but not arterial thrombosis ( Table 1 ). 23 …”

Thrombosis Risk Assessment in Myeloproliferative Neoplasm—Is There a Role for Viscoelastic Testing?

“…10,12 In contrast to Zhang et al who reported JAK2 V617F variant allele frequency !50% to be one of the independent risk factors affecting arterial thrombosis but not venous thrombosis, 12 Guglielmelli et al reported JAK2 V617F variant allele frequency !50% to be an independent risk factor for venous thrombosis (hazard ratio 4.0, p < 0.001) but not for arterial thrombosis (hazard ratio 0.9, p ¼ 0.8). 13 Meanwhile, the calreticulin (CALR) mutation, particularly the type 2-like CALR mutation, carries a more indolent course with fewer thrombotic events compared with JAK2 V617F and MPLmutated patients. 14,15 The International Prognostic Score for Thrombosis in ET (IPSET) has been validated to help clinicians estimate the probability of thrombotic events in ET and more recently pre-PMF.…”