Eltrombopag-Associated Cerebral Venous Sinus Thrombosis in Children

To the Editor: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by a low platelet count resulting from platelet destruction and impaired platelet production. In children with ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL and do not respond to first-line treatment, the American Society of Hematology guideline panel suggests the use of thrombopoietin receptor agonists (TPO-RAs).1 Eltrombopag, as the earliest nonpeptide and small molecule oral TPO-RA, can be administered orally and belongs to the current second-line treatment options for ITP.2,3 TPO-RA could activate the TPO receptor and stimulate the JAK2/STAT5 pathway to increase megakaryocyte progenitor proliferation and platelet production.4 The patient, a 3-year-old girl, was diagnosed with ITP since November 2020. According to the first-line treatment regimen outlined in the “Chinese Children's Primary Immune Thrombocytopenia Diagnosis and Treatment Adaptation Guide,” the patient received methylprednisolone sodium succinate and gamma globulin but did not respond well. After the addition of rituximab targeted therapy, the patient's platelet count normalized briefly before declining again, leading to multiple hospitalizations due to recurrent thrombocytopenia with a bleeding grade of 3 (nasal bleeding). The initial dose of oral eltrombopag (25 mg qd) was found to be unsatisfactory after 2 weeks, as the platelet count remained below 50 × 109/L. Subsequently, the dosage was increased to 50 mg qd, resulting in a gradual rise in platelet count to 87 × 109/L. It is recommended that the child's condition be monitored regularly and drug dosages adjusted accordingly. However, the child did not adhere to scheduled follow-up appointments. Four months later, the patient was admitted to the hospital with a diagnosis of thrombocytopenia for 8 months, accompanied by vomiting and headache for 1 day. The blood routine examination revealed a platelet count of 976 (×109/L) (Figure 1), whereas liver function tests showed elevated levels of alanine aminotransferase at 155.2 (μ/L) and aspartate aminotransferase at 58.78 (μ/L). A head magnetic resonance imaging demonstrated small thrombi in the posterior margin of the superior sagittal sinus, left transverse sinus, and sinus confluence area (Figure 2). The child had no other apparent risk factors for cerebral venous sinus thrombosis and no other complications. After treatment with eltrombopag to increase platelet count, the child failed to follow up with the doctor in a timely manner to adjust the medication dosage, resulting in secondary thrombocytosis and cerebral thrombosis.FIGURE 1.: Law of Platelet Change.FIGURE 2.: The magnetic resonance angiography of the head indicated small thromboses at the posterior margin of the superior sagittal sinus and at the left transverse sinus and sinus confluence.After admission, the patient discontinued eltrombopag and received symptomatic and supportive treatments including subcutaneous injection of low molecular weight heparin sodium for anticoagulation, aspirin and dual antiplatelet therapy with dextromethorphan, glutathione for liver protection, mannitol for dehydration, and gastric rehydration. After 18 days, the patient's headache improved and platelet count decreased to 24 × 109/L. After immunoglobulin treatment, the patient's platelet count increased to 100 × 109/L (Figure 1). The head magnetic resonance angiography revealed the disappearance of the thrombus after 20 days. After discharge, the patient continued to take eltrombopag (25 mg qd). Subsequent dynamic reviews showed that the patient's platelet count fluctuated between 30 and 100 × 109/L. The magnetic resonance angiography of the head indicated small thromboses at the posterior margin of the superior sagittal sinus and at the left transverse sinus and sinus confluence. The use of eltrombopag as a second-line treatment is recommended in the “Chinese Guidelines for the Changes in the Diagnosis and Treatment of Primary Immune Thrombocytopenia in Children (2021 Edition).” It should be administered to children with immune thrombocytopenia when first-line treatments are ineffective. The most common adverse reaction is liver function damage, and caution should also be taken regarding thrombosis associated with eltrombopag therapy for platelet elevation. Although this adverse reaction has only been reported in adults, it has not been observed in children. One case involved a child who did not receive regular monitoring after taking eltrombopag and failed to adjust the dosage promptly, resulting in intracranial venous sinus thrombosis. After receiving appropriate treatment and timely adjustment of drug dosage, the patient's condition improved without further thrombotic complications. In conclusion, vigilance against thrombotic complications is essential when using eltrombopag, along with regular monitoring and dose adjustments, to prevent such occurrences.