Platelet Count over Time Is Not Associated with Incidence of Thrombosis in Patients with Essential Thrombocythemia

Background:

Past controlled studies suggest that platelet count should be controlled with cytoreductive agents to prevent thrombosis in patients with essential thrombocythemia (ET) with high risk features. Platelet count within between 400 and 600 × 10⁹ /L is usually used as a therapeutic target in clinical practice. However, it is still unclear that platelet count over time itself is a risk factor for thrombosis. We evaluated the impact of platelet count over time on the incidence of thrombotic events in ET patients in our institution.

Methods:

This study included ET patients who were diagnosed in NTT Medical Center Tokyo between March 2003 and September 2023. We introduced a variable called controlled platelet count (CPC) to represent platelet count over the entire time course in each patient. When the sum of each time period where a patient's platelet count is over X is equal to 20.0% of the period between diagnosis and thrombotic event or end of follow-up, whichever comes first, we defined the X as CPC. To confirm that controlling platelet count lower than 600 × 10⁹ /L (this cutoff was based on the study by Cortelazzo et al.) is effective to reduce the incidence of thrombotic events, we compared the cumulative incidence of thrombosis between CPC below 600 × 10⁹ /L (CPC < 600) group and above 600 × 10⁹ /L (CPC > 600) group using the method proposed by Gray. Furthermore, to assess whether CPC was independent risk factor for thrombosis and to identify the features associated with the incidence of thrombosis, we performed multivariate analysis that assessed the factors affecting thrombosis including CPC, which was treated as continuous variable and other variables. Death without thrombosis was defined as a competing event and P values and hazard ratios were calculated with the use the Fine-Gray model. Patients were classified as having cardiovascular risk factor(s), if they met one or more of the following criteria: current smoking, hypertension requiring therapy; diabetes requiring hypoglycemic therapy; hyperlipidemia requiring therapy. We considered only major vasoocclusive events, including ischemic stroke, cerebral transient ischemic attacks, acute myocardial infarction, peripheral arterial thrombosis, and venous thromboembolism as thrombotic events for this study.

Results:

A total of 133 consecutive patients were analyzed, 49 of whom were in CPC < 600 group and 84 were in CPC > 600 group. Mean platelet counts in CPC < 600 group maintained around 400 × 10⁹ /L and in CPC > 600 group maintained around 800 × 10⁹ /L over time demonstrating CPC was a good indicator of platelet count over time. Patients in CPC < 600 group was older than those in CPC > 600 group (median age, 69 years vs. 60 years, respectively; P=0.008). Blood count at diagnosis, mutation status and proportion of patients with previous history of thrombosis were comparable between groups. More patients in CPC < 600 group was treated with hydroxyurea than those in CPC > 600 group (73.5 % vs. 51.2 %, respectively; P=0.017). With a median follow-up time for the entire population was 73.0 months (range:1.8-250.5), 10 patients developed major thromboses (5 (10.2%) in CPC < 600 group and 5 (6.0%) in CPC > 600 group ) with 7 arterial and 4 venous thrombotic events. Cumulative incidence of thrombosis was not significantly different between the two groups (HR, 1.34; 95% CI, 0.39 to 4.61; p = 0.641). In multivariate analysis including age ≥ 60, cardiovascular risk factors, JAK2 mutation, aspirin or other antiplatelet therapy and CPC, CPC was not significant for thrombosis (HR, 0.99; 95% CI, 0.95 to 1.04; p = 0.697). In the multivariate model, we did not incorporate past history of thrombosis, which was reported as a risk factor in past several studies because none of patients who developed thrombosis had history of thrombosis in this cohort. We identified cardiovascular risk factors as the only independent risk for thrombosis (HR, 6.24; 95% CI, 1.04 to 37.36; p = 0.045).

Conclusions:

In the present study, we found no association between platelet count over time and the incidence of thrombotic events. This real-world data is inconsistent with the current recommendations to initiate cytoreductive therapy to reduce thrombosis in ET patients. Our patient population had low incidence of thrombosis; therefore, our sample size was limited. Additional analyses will expand our understanding of the impact of platelet count over time on thrombosis and of the necessity of cytoreductive therapy.

Usuki:Chugai Pharmaceutical Co., Ltd.: Consultancy, Research Funding; Ohara Pharmaceutical Co., Ltd.: Consultancy; Astellas Pharma Inc.: Consultancy, Research Funding; AbbVie G.K.: Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals, Inc.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding; Eisai Co., Ltd.: Consultancy, Research Funding; Incyte Biosciences Japan G.K.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Consultancy, Honoraria, Research Funding; MSD K.K.: Research Funding; Nippon Shinyaku Co., Ltd.: Consultancy, Honoraria, Research Funding; Novartis Pharma K.K.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Consultancy, Research Funding; Pfizer Japan Inc.: Honoraria; Sanofi K.K.: Consultancy, Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding; Yakult Honsha Co., Ltd.: Research Funding; Amgen K.K.: Consultancy, Research Funding; Janssen Pharmaceutical K.K.: Research Funding; Alnylam Japan K.K.: Consultancy.