High-normal and mildly elevated bilirubin levels in prefibrotic primary myelofibrosis patients are associated with lower thrombotic risk.

High-normal or mildly elevated bilirubin concentrations without apparent significance are commonly observed in clinical practice. Several observations in various chronic diseases associate them with reduced risk of metabolic and cardiovascular diseases, likely due to their antioxidant and anti-inflammatory activity. We aimed to investigate potential clinical and prognostic associations of high-normal to mildly elevated bilirubin in patients with prefibrotic primary myelofibrosis (pre-PMF), a chronic myeloproliferative neoplasm with high inflammatory and thrombotic burden. We retrospectively analyzed clinical and prognostic associations of bilirubin levels in a total of 82 pre-PMF patients diagnosed and treated in six Croatian hematology centers. Patients with apparent liver disease or hemolytic anemias were excluded from analysis. Among 82 evaluated patients, 54 (66.7%) were JAK2 mutated; 14 (17.5%) had prior thrombosis. Median age was 66 years. Incidence rates for thrombosis and bleeding were 2.02% and 1.26% patient-years, respectively. Median bilirubin levels were 11.9 µmol/L. Patients were stratified at a data-derived ≤11/>11 µmol/L cutoff for thrombotic risk evaluation. Although higher-bilirubin patients were more likely to belong to higher revised-IPSET-thrombosis categories, to be of male sex, and to have lower platelet and lymphocyte counts, they experienced significantly lower thrombotic risk compared to lower-bilirubin patients (0.47% and 3.81% patient-years, respectively). No significant association with major bleeding, nor with mortality, was observed. In the multivariate Fine and Gray regression model, higher-bilirubin (sHR 0.029 (0.006-0.13), p < 0.001) was independently associated with lower thrombotic risk, whereas older age (sHR 1.21 (1.04-1.41), p = 0.013) and male sex (sHR 6.75 (1.45-31.4), p = 0.015) were mutually independent predictors of higher thrombotic risk.