Potential Anti-Thrombotic Effect without Accompanying Hemorrhage with Fostamatinib Use in Patients with Immune Thrombocytopenia

Background Immune thrombocytopenia (ITP) results from autoimmune antibody-mediated destruction of platelets. Bruising and bleeding are hallmarks of ITP, but thromboembolic events (TEEs) are also observed in ITP patients, even thrombocytopenic ones. In population-based cohort studies, chronic ITP patients had two-fold higher risk of a venous TEE compared to the general population.1 The risk of venous or arterial TEE is further elevated in splenectomized ITP patients and those on thrombopoietin receptor agonists (TPO-RAs). Other risk factors include: age > 60 years, prolonged corticosteroid treatment, diabetes, hypertension, coronary disease, history of TEEs, presence of anti-phospholipid antibodies, chronic kidney disease, and male sex. Fostamatinib, an inhibitor of spleen tyrosine kinase (SYK), is approved for treatment of thrombocytopenia in adults with ITP. Extensive preclinical data suggest that inhibition of SYK signaling may also have an anti-thrombotic effect. In a model of acute stroke, mice with platelet-specific SYK deficiency were protected from aortic thrombosis and also had diminished size of brain infarction with only marginal effect on hemostasis.2 These results were reproduced by a SYK inhibitor in this model.2 We assessed rates of thrombosis among ITP patients treated with fostamatinib compared to those reported with TPO-RAs. Methods We reviewed the incidence of TEEs during fostamatinib clinical trials in ITP, including 2, randomized, double-blind, placebo-controlled, phase 3, multicenter clinical trials and an open-label extension study. The incidence of TEEs with TPO-RAs during published phase 3 clinical trials and post-phase 3 extension studies was also reviewed. Results The study population comprised 145 ITP patients who received fostamatinib and included 37 (26%) patients >65 years, 51 (35%) splenectomized patients, and 58 (40%) male patients. The 3 fostamatinib clinical trials represent 163 patient-years of fostamatinib exposure. The only reported TEE was a transient ischemic attack (0.7%), which resolved spontaneously in a patient with pre-existing atherosclerosis. The rate of TEEs reported in ITP patients receiving TPO-RAs in multiple studies ranged from 0 to 9% (Table). Discussion The rate of TEEs observed in ITP patients receiving fostamatinib was very low (< 1%) in comparison with the rates of TEEs reported in ITP patients receiving a TPO-RA (up to 9%). ITP patients have higher levels of prothrombin fragments 1 + 2, D-dimer, PAI-