Platelet Factor 4 (PF4) Levels Are Inversely Correlated with Steady-State Platelet Counts and with Nadir Counts in Chemotherapy-Induced Thrombocytopenia (CIT),

Abstract 3527

PF4 (CXLC4) is a member of the C-X-C family of chemokines and has been shown to be a negative autocrine of megakaryopoiesis in vitro and in animal models of CIT and radiation-induced thrombocytopenia (RIT). In animal models, steady-state platelet counts, as well as duration of thrombocytopenia and nadir platelet count after chemotherapy or radiation therapy were inversely correlated with platelet PF4 levels. We designed a clinical study to examine the role of PF4 in human subjects treated with chemotherapy. We examined platelet PF4 levels in 97 pediatric patients treated for standard risk leukemia in a single institution study. All patients completed therapy since January 1, 1999. Samples were collected at the completion of therapy from all patients, and a subset of randomly selected patients had multiple samples collected to determine intra-subject variability of assessment. PF4 levels were no different in this cohort from age matched normal controls. While there was significant inter-individual variability in the cohort, there was no significant difference in an individual between samples collected up to 1 year apart. There was an inverse correlation between platelet PF4 levels and steady-state platelet count (r=-0.2107 95% CI: −0.39 to −0.01, p=0.0383), yet we found no correlation with plasma thrombopoietin (TPO) or CXCL11 (stromal derived factor-1) levels, both of which are known positive regulators of megakaryopoiesis. We then examined the effect of PF4 on CIT by reviewing medical records of these patients, extracting the nadir platelet count and transfusion records for delayed intensification. There was an inverse correlation between platelet PF4 content and nadir platelet count during delayed intensification (r=-0.2087 95% CI: -0.41 to 0.01, p=0.0316). In addition, subjects who required platelet transfusion during delayed intensification had significantly higher platelet PF4 levels when compared to those subjects who did not require transfusion (11.48 ± 8.2 IU/10⁸ platelets versus 5.23 ± 4.7 IU/10⁸ platelets, p=0.003). All of the patients with PF4 levels > 1SD above the mean (>18 IU/10⁸ platelets) were transfused, while only 28% of patients with PF4 levels > 1 SD below the mean (< 4 IU/10⁸ platelets) (overall 58% of patients were transfused). In contrast, there was no difference between plasma TPO or CXCL11 levels between those patients who did and did not require transfusion. These clinical data are not only consistent with our previously published animal studies; they show that platelet PF4 levels may be the first identified, patient-specific predictor of risk of transfusion during chemotherapy and may allow for stratified dose-intensification in patients with cancer. These studies also suggest new approaches for modifying megakaryopoiesis and developing novel strategies to moderate CIT and possibly RIT.