Abstract
Thrombopoietin receptor agonists (TPO-RAs) are an effective treatment for refractory immune thrombocytopenia (ITP). However, the use of TPO-RAs is limited for ITP in pregnant women due to concerns about fetal toxicity. In this study, we examined the effects of romiplostim, one of the TPO-RAs, on pregnant mice. The mice were injected subcutaneously with romiplostim (1, 5, 10, 30, and 100 μg/kg) on gestational days (GD) 1, 8, and 15. We evaluated maternal and fetal platelet and megakaryocyte counts (MK), fetal weight at birth, placental morphology, and miscarriage rates. Romiplostim increased platelet and MK counts in pregnant mice at all doses and in fetuses at doses above 10 µg/kg. Fetal weight at birth was slightly reduced at a dose of 100 μg/kg, but there were no significant differences in placental weight, spiral artery wall thickness, placental growth factor signal changes, or the rate of resorption at that dosage. The dose of romiplostim used clinically for ITP patients (1–10 μg/kg) did not show any adverse effects on pregnant mice. Although the results of the present study are encouraging, until there are more conclusive data, the use of romiplostim should be evaluated individually in severe, life-threatening cases, and all relevant ethical aspects should be considered.
Highlights
Immune thrombocytopenia (ITP) is an autoimmune disease characterized by persistent thrombocytopenia due to the binding of antibodies to platelet antigens and the premature destruction of platelets by the reticuloendothelial system, mainly in the spleen [1]
ITP is often exacerbated during pregnancy [4], and it is important to maintain a safe maternal platelet count because purpura, epistaxis, and gastrointestinal bleeding may occur with a severe decrease in platelet count, increasing the risk of postpartum hemorrhage [5]
In the histological images (H&E) of femoral bone marrow of the pregnant mice treated with 100 μg/kg of romiplostim on GD18, a prominent increase in megakaryocyte counts (MK) counts could be observed, compared to the control group (Figure 3A,B)
Summary
Immune thrombocytopenia (ITP) is an autoimmune disease characterized by persistent thrombocytopenia due to the binding of antibodies to platelet antigens and the premature destruction of platelets by the reticuloendothelial system, mainly in the spleen [1]. ITP often occurs in women between the ages of 20 and 40 years and is often associated with pregnancy or diagnosed only after pregnancy. ITP is often exacerbated during pregnancy [4], and it is important to maintain a safe maternal platelet count because purpura, epistaxis, and gastrointestinal bleeding may occur with a severe decrease in platelet count, increasing the risk of postpartum hemorrhage [5]. The first-line therapy for pregnant women with ITP recommended by the American. Society of Hematology guidelines is either intravenous immunoglobulin (IVIg) or corticosteroids [6], but there are scattered cases of refractory ITP that do not respond to treatment. Azathioprine, cyclosporine, and rituximab are used for the treatment of refractory ITP, but the use of these drugs is limited in pregnant women because of their impact on the fetus [7].
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