Is Thromboembolism in Cancer Patients Treated with Erythropoietic Stimulating Agents Related to Thrombocytosis and Iron Restricted Erythropoiesis?.
Authors: Henry David H. , Dahl Naomi V. , Auerbach Michael 
Published: April 2020

Abstract
Venous thromboembolism (VTE) is a frequent complication of cancer and chemotherapy. Increased risk is associated with many factors including use of erythropoietic stimulating agents (ESA) and with increased platelet count (Khorana et al. Cancer 2005). The increase in platelet count observed with ESA use may be associated with functional iron deficiency as ESA therapy induces iron-restricted erythropoiesis, and iron deficiency can cause reactive thrombocytosis. VTE have been associated with thrombocytosis in iron deficient patients, and although occurance is extremely rare in otherwise-healthy individuals, patients who are already at high risk may be particularly susceptible. To explore this hypothesis we examined the association between VTE incidence and changes in platelet count in a post hoc analysis of our prospective, randomized, controlled, multicenter trial, which had compared effects of IV iron, oral iron, and no iron, on Hb response to ESA therapy in anemic cancer patients receiving chemotherapy (Henry et al. The Oncologist 2007). Major trial inclusion criteria: pt starting chemotherapy cycle, Hb &lt;11g/dL, ferritin &gt;100 ng/mL or transferrin saturation &gt;15%. Major exclusions: recent transfusion, ESA, or IV iron use, infection. All pts received epoetin alfa (40,000 U SQ/Wk for first 4 wks, then dose-adjusted per protocol). Pts were randomized to: No iron (ESA alone), PO FeSO4 325 mg tid, or IV ferric gluconate 125 mg IV weekly, for 8 weeks. Odds ratios (OR) for likelihood of occurrence of thromboembolic adverse events, and incident rate ratios (IRR) for their rate of occurrence were analyzed with logistic and Poisson regression, respectively. Nineteen of the 187 patients enrolled experienced 29 thromboembolic events (Table 1). The incidence of thromboembolism was fourfold greater among patients whose platelet counts increased from baseline to values ≥350,000 cells/μL at any time during the study (IRR 4.4, P=0.001). These patients were approximately three times more likely to experience at least one thromboembolic event than other patients (OR 2.9, P=0.036). Patients randomized to receive IV iron were significantly less likely to experience a post baseline platelet count of ≥350,000 cells/μL than those receiving oral iron or no iron (IRR 0.7, P=0.013). Furthermore, IV iron treatment was also associated with a 40% reduction in the rate of thromboembolic events (IRR 0.6, P=0.2), which was not independent of changes in platelet status. These findings suggest one possible mechanism for the increase in VTE associated with ESA use: that iron-restricted erythropoiesis induced by ESA therapy can lead to elevation in platelet count, providing an additional risk factor for VTE for patients who are already predisposed. We encourage a retrospective review of other ESA clinical trials and prospective trials to test this hypothesis, and whether or not intravenous iron, in addition to improving responsiveness to ESA by preventing iron-restricted erythropoiesis, can also decrease the incidence of VTE in such patients in order to enhance the safety of ESA therapy.
Table 1 Thromboembolic Adverse Event* No Iron (N=63) Oral Iron (N=61) IV Iron (N=63) Pts Events Pts Events Pts Events *COSTART term Cerebrovascular Accident 0 0 1 1 2 2 Pulmonary Embolism 1 1 2 3 1 1 Ischemia, cerebral 0 0 1 1 0 0 Thrombophlebitis 1 1 2 2 1 1 Thrombophlebitis, deep 6 9 2 4 3 3 Overall 6 11 7 11 6 7