clinical topic updates
Progressive Leukocytosis and Thrombotic Risk in Polycythemia Vera
Along with age and history of thrombosis, leukocytosis is an independent risk factor for thrombotic events in patients with polycythemia vera (PV). Leukocytosis may increase thrombotic risk in those with PV through multiple mechanisms that result in the disruption of hemostasis toward a prothrombotic state.
Associate Professor of Clinical Internal Medicine
“There is a growing consensus that leukocytosis may be an indication for cytoreductive therapy in patients with PV.”
There is a growing consensus that leukocytosis may be an indication for cytoreductive therapy in patients with PV. Leukocytosis has been identified as an independent risk factor for thrombosis in patients with PV, and the degree of leukocytosis associated with thrombosis has ranged from greater than 7000/µL to greater than 15,000/µL. The European LeukemiaNet recently issued a recommendation to consider cytoreductive therapy when the patient’s leukocyte count exceeds 15,000/µL. From the clinician’s perspective, it is concerning when a patient’s leukocyte count is that high at diagnosis or at any point during therapy. In patients with PV, leukocytosis often occurs at presentation, along with other factors such as older age or history of prior thrombosis; however, it can also occur in progressive disease, along with splenomegaly and thrombocytosis. In addition to progressive symptoms, leukocytosis is a warning sign that we watch for when identifying a progressive picture. Thus, the risk of thrombosis is increased in patients with PV and leukocytosis at baseline and in those who develop leukocytosis later during the course of their disease.
In trying to understand how leukocytosis might increase thrombotic risk, there are several interesting leads from the biomedical research (eg, neutrophils release reactive oxygen species and intracellular proteases, which can act on endothelial cells and platelets and may favor a prothrombotic state). The JAK2 V617F mutation has been associated with increased leukocyte counts, and it has been theorized that leukocytosis may be part of the observed thrombogenic influence of the JAK2 mutation. Using in vitro and in vivo models, Guy et al found that vascular endothelial cell expression of the JAK2 V617F mutation promoted a prothrombotic state due to increased endothelial P-selectin expression.
Treatments such as aspirin and phlebotomy do not reduce elevated white blood cell counts. We already have recommendations for lowering hematocrit levels and the risk of thrombosis in patients with PV, and we may soon have specific recommendations for lowering white blood cell counts in those with PV and leukocytosis.
Abdulkarim K, Samuelsson J, Johansson P, Andréasson B. Risk factors for vascular complications and treatment patterns at diagnosis of 2389 PV and ET patients: real-world data from the Swedish MPN Registry. Eur J Haematol. 2017;98(6):577-583.
De Stefano V, Za T, Rossi E, et al; GIMEMA Chronic Myeloproliferative Neoplasms Working Party. Leukocytosis is a risk factor for recurrent arterial thrombosis in young patients with polycythemia vera and essential thrombocythemia. Am J Hematol. 2010;85(2):97-100.
Griesshammer M, Kiladjian JJ, Besses C, et al. Thromboembolic events in polycythemia vera. Ann Hematol. 2019;98(5):1071-1082.
Guy A, Gourdou-Latyszenok V, Le Lay N, et al. Vascular endothelial cell expression of JAK2V617F is sufficient to promote a pro-thrombotic state due to increased P-selectin expression. Haematologica. 2019;104(1):70-81.
Landolfi R, Di Gennaro L, Barbui T, et al; European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP). Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood. 2007;109(6):2446-2452.