C-MPL信号通路与育龄期女性血液病患者生殖能力

… IL-11 is to maintain female fertility.19 The pleiotropic actions of … The generation of mice deficient in TPO or its receptor c-Mpl … of IL-l 1 signaling in TPO-unresponsive (c-Mpl null) mice has …

Pregnancy in the context of myeloproliferative neoplasms (MPN) poses unique fetal and maternal challenges. Current literature in this regard mostly involves essential thrombocythemia (ET) and less so polycythemia vera (PV) or myelofibrosis. In ET, live birth rate is estimated at 70% with first trimester fetal loss (˜ 30%) as the major complication. Risk of pregnancy‐associated complications is higher in PV, thus mandating a more aggressive treatment approach. Herein, we appraise the relevant literature, share our own experience and propose management recommendations. Aspirin therapy may offer protection against fetal loss; however the additive benefit of systemic anticoagulation or cytoreductive therapy, in the absence of high risk disease, is unclear. We recommend cytoreductive therapy in the form of interferon alpha in all high risk and select low‐risk ET and PV patients with history of recurrent fetal loss, prominent splenomegaly or suboptimal hematocrit control with phlebotomy. In addition, all women with PV should maintain strict hematocrit control <45% with the aid of phlebotomy. Systemic anticoagulation with low molecular weight heparin is advised in patients with history of venous thrombosis. Further clarification awaits prospective clinical trials that implement risk adapted therapeutic interventions.

… another pregnancy in order to achieve complete hematological response. They had normal … miscarriage versus none in MPL/CALR/triple negative pregnancies (p = 0.027)). Outside of …

… Subsequently, MPLW515K and other exon 10 MPL mutations … with peripheral blood mutation screening for JAK2V617F. … Women of child-bearing potential and those who are pregnant …

Some childhood cancers can arise in utero and then regress at birth, but the cues that permit malignant proliferation in utero as opposed to postnatal life are often unclear. Transient abnormal myelopoiesis (TAM) is a human fetal liver leukemia driven by GATA1s mutations and a rare exemplar of a spontaneously resolving cancer when blood formation shifts from liver to bone marrow (BM) during development. Here we show that the cytokine receptor CSF2RB is aberrantly upregulated in TAM cells because it is a GATA2 target that escapes repression by GATA1s. Pathologically expressed CSF2RB unexpectedly interacts with the thrombopoietin receptor MPL to prolong JAK-STAT signaling by fetal-liver produced THPO, driving GATA1s-mutant cell expansion. TAM can transform into myeloid leukemia of Down syndrome (ML-DS) upon acquisition of additional mutations. We further show that the ML-DS driver CSF2RB A455D forces MPL dimerization resulting in constitutive JAK-STAT activation, bypassing THPO dependence in the fetal-liver niche, thereby enabling proliferation in the BM. Conversely, base-editing reversion of another ML-DS JAK-STAT-activating mutation, JAK3 A572V, restores THPO dependence. These results identify a cytokine gate that developmentally restricts GATA1s oncogenic competence, reconciling why TAM expands in the fetal liver yet resolves after birth, revealing a niche-specific, therapeutically targetable dependency.

… myeloproliferative neoplasms are hematological disorders … neoplasms mainly the JAK2V617F mutation, the Mpl receptor, … an independent risk factor for pregnancy complications in ET …

The thrombopoietin (TPO) gene expression in human ovary and cancer cells from patients with ovarian carcinomatosis, as well as several cancer cell lines including MDA-MB231 (breast cancer), K562 and HL60 (Leukemic cells), OVCAR-3NIH and SKOV-3 (ovarian cancer), was performed using RT PCR, real-time PCR, and gene sequencing. Human liver tissues are used as controls. The presence of TPO in the cells and its regulation by activated protein C were explored by flow cytometry. TPO content of cell extract as well as plasma of a patient with ovarian cancer was evaluated by ELISA. The functionality of TPO was performed in coculture on the basis of the viability of a TPO-dependent cell line (Ba/F3), MTT assay, and Annexin-V labeling. As in liver, ovarian tissues and all cancer cells lines except the MDA-MB231 express the three TPO-1 (full length TPO), TPO-2 (12 bp deletion), and TPO-3 (116 pb deletion) variants. Primary ovarian cancer cells as well as cancer cell lines produce TPO. The thrombopoietin production by OVCAR-3 increased when cells are stimulated by aPC. OVCAR-3 cell's supernatant can replace exogenous TPO and inhibited TPO-dependent cell line (Ba/F3) apoptosis. The thrombopoietin produced by tumor may have a direct effect on thrombocytosis/thrombosis occurrence in patients with ovarian cancer.

… TPO is involved in controlling ovarian function. Direct involvement of TPO in controlling ovarian function … mRNA expression of (a) Thrombopoietin and (b) Thrombopoietin receptor in the …

Thrombopoietin mimic peptide (TMP) is a novel thrombopoietin receptor agonist. In this report, we evaluated the potential toxicity of TMP in repeat-dose toxicity and reproductive/developmental toxicity studies (segment Ⅰ, Ⅱ, Ⅲ). TMP was administered subcutaneously to Sprague-Dawley (SD) rats at 5, 15 or 50 mcg/kg. In repeat-dose toxicity study, the rats were administrated three times a week for 26 week with a 4-week recovery. TMP could produce anti-drug antibodies and induce platelet counts increase, megakaryocyte proliferation. While platelet counts decreased gradually and returned to normal after 4 weeks in male rats. Other significant findings included myelofibrosis of bone marrow, hepatic extramedullary hematopoiesis, splenic lymphocytic depletion and bone hyperostosis. All treatment-related effects were reversed following recovery. The NOAEL of repeat-dose toxicity in female rats is 5 mcg/kg. In the reproductive/developmental toxicity (segment Ⅰ, Ⅲ), no deaths occurred, and no general toxicological effects or abnormal reproductive functions were observed. In embryo-fetal developmental toxicity study (segment Ⅱ), the number of resorbed fetuses in the 50 mcg/kg group was significantly increased. The NOAEL as related to reproductive/developmental toxicity in these rats was 15 mcg/kg.

The treatment of immune thrombocytopenia (ITP) in adults has evolved rapidly over the past decade. The second-generation thrombopoietin receptor agonists (TPO-RAs), romiplostim, eltrombopag, and avatrombopag are approved for the treatment of chronic ITP in adults. However, their use in pregnancy is labeled as category C by the United States Food and Drug Administration (FDA) due to the lack of clinical data on human subjects. ITP is a common cause of thrombocytopenia in the first and second trimester of pregnancy, which not only affects the mother but can also lead to thrombocytopenia in the neonatal thrombocytopenia secondary to maternal immune thrombocytopenia (NMITP). Corticosteroids, intravenous immunoglobulins (IVIGs) are commonly used for treating acute ITP in pregnant patients. Drugs such as rituximab, anti-D, and azathioprine that are used to treat ITP in adults, are labeled category C and seldom used in pregnant patients. Cytotoxic chemotherapy (vincristine, cyclophosphamide), danazol, and mycophenolate are contraindicated in pregnant women. In such a scenario, TPO-RAs present an attractive option to treat ITP in pregnant patients. Current evidence on the use of TPO-RAs in pregnant women with ITP is limited. In this narrative review, we will examine the preclinical and the clinical literature regarding the use of TPO-RAs in the management of ITP in pregnancy and their effect on neonates with NMITP.

… All of the changes in hematology and clinical chemistry parameters are reported as mean … ; and Mann-Whitney U test in reproductive toxicity studies) at a significance level of 5% or less. …

rescue use. Information on early gestational exposure, including reports involving eltrombopag, romiplostim, recombinant human thrombopoietin, or hetrombopag, remains rare [2,3,4,9,10]. Given evidence of developmental toxicity in animal models, current guidance advises avoiding elective TPO-RA use during pregnancy, particularly in the first trimester; therefore, our observations should be interpreted strictly as descriptive and not as evidence of safety. Although uncommon, prolonged or earlier exposure has been reported with heterogeneous outcomes. Patil et al. [11] described romiplostim use throughout pregnancy with platelet control but significant neonatal complications, highlighting unresolved safety concerns. In contrast, Mendicino et al. [12] reported eltrombopag use throughout pregnancy, including the first trimester, without maternal or neonatal complications. In their comprehensive review, Rottenstreich and Bussel [3] emphasized that first-trimester exposure remains infrequent and that available data are insufficient to draw firm conclusions during organogenesis. Our case illustrates a practical, guideline-concordant approach in which inadvertent early TPO-RA exposure was managed by prompt drug discontinuation, multidisciplinary monitoring, and IVIG-based therapy tailored to gestational platelet targets [1]. In conclusion, unintended first-trimester exposure to TPO-RAs does not necessarily mandate pregnancy termination when agents are discontinued promptly and alternative therapy is instituted. Nevertheless, elective use of TPO-RAs during pregnancy, and especially during organogenesis, should be avoided, and women of reproductive age require careful counseling. Further prospective data are needed to define safety across all trimesters.

Chemotherapeutic agents and radiotherapy are highly effective in treating malignancies. However, they carry a significant risk of harming the gonads and may lead to endocrine dysfunction and reproductive issues. This review outlines the molecular mechanisms of gonadotoxic therapies, focusing on radiation, alkylating agents, and platinum compounds. It discusses the loss of PMFs due to gonadotoxic exposure, including DNA double-strand breaks, oxidative stress, and dysregulated signaling pathways like PI3K/PTEN/Akt/mTOR and TAp63-mediated apoptosis. Furthermore, it explores strategies to mitigate gonadal damage, including GnRH agonists, AMH, imatinib, melatonin, sphingolipid metabolites, G-CSF, mTOR inhibitors, AS101, and LH. These therapies, paired with existing fertility preservation methods, could safeguard reproductive and hormonal functions and improve the quality of life for young cancer patients. Despite the progress made in recent years in understanding gonadotoxic mechanisms, gaps remain due to questionable reliance on mouse models and the lack of models replicating human ovarian dynamics. Long-term studies are vital for wider analyses and exploration of protective strategies based on various animal models and clinical trials. It is essential to verify that these substances do not hinder the anti-cancer effectiveness of treatments or cause lasting DNA changes in granulosa cells, raising the risk of miscarriages and infertility.

Management of immune thrombocytopenia (ITP) during pregnancy can be challenging since treatment choices are limited. Thrombopoietin receptor agonists (Tpo-RAs), which likely cross the placenta, are not recommended during pregnancy. To better assess safety and efficacy of off-label use of Tpo-RA during pregnancy, a multicenter observational and retrospective study was set up. Results from 15 pregnant women with ITP (17 pregnancies and 18 neonates) treated with either eltrombopag (N=8) or romiplostim (n=7) during pregnancy, including 2 patients with secondary ITP, were analyzed. Median time of Tpo-RA exposure during pregnancy was 4.4 weeks [range: 1-39 weeks]; the indication for starting Tpo-RA was preparation for delivery in 10/17 (58%) pregnancies whereas 4 had chronic refractory symptomatic ITP and 3 were on eltrombopag when the pregnancy started. Regarding safety, neither thromboembolic events among mothers nor Tpo-RA-related fetal or neonatal complications were observed except for one case of neonatal thrombocytosis. Response to Tpo-RA was achieved in 77% of cases, mostly in combination (70% of responders) with concomitant ITP therapy. Based on these preliminary findings, temporary off-label use of a Tpo-RA for severe and/or refractory ITP during pregnancy seems safe for both mother and neonate and likely to be helpful especially prior to delivery.

The introduction of thrombopoietin receptor agonists (TPO‐RAs) led to a paradigm shift in the management of immune thrombocytopenia (ITP). However, TPO‐RAs are not approved for use during pregnancy due to the absence of evidence and concerns for possible effects on the fetus due to their expected transplacental transfer. This comprehensive review examines the safety and efficacy of TPO‐RA in 45 pregnancies of women with ITP (romiplostim n = 22; eltrombopag n = 21; both in the same pregnancy n = 2). Mothers experienced failure of the median of three treatment lines during pregnancy prior to TPO‐RA administration. A platelet response (>30 × 109/L) was seen in 86.7% of cases (including a complete response >100 × 109/L in 66.7%) and was similar between eltrombopag and romiplostim (87.0% and 83.3%, p = 0.99). The maternal safety profile was favourable, with no thromboembolic events encountered. Neonatal thrombocytopenia was noted in one third of cases, with one case of ICH grade 3, and neonatal thrombocytosis was observed in three cases. No other neonatal adverse events attributable to TPO‐RAs were seen. This review suggests that the use of TPO‐RA during pregnancy is associated with a high response rate and appears safe. Nevertheless, TPO‐RA should not be routinely used in pregnancy and should be avoided in the first trimester until further evidence is accumulated.

Key Points rhTPO is a potentially effective and safe treatment option for ITP during pregnancy.

Immune thrombocytopenia (ITP) presents unique challenges in the peripartum setting. The diagnosis of ITP is similar to the nonpregnant patient except pregnancy related causes of thrombocytopenia must be considered. Management of ITP will change over the course of pregnancy and closer monitoring is critical as delivery approaches when the recommended platelet goal increases from 20×10–30×10/L to above 50×10/L for a vaginal delivery. If an epidural is required, the platelet count should be above 70×10/L. The mode of delivery is based on obstetrical indications. First line therapies are glucocorticoids or intravenous immunoglobulin (IVIG). Many second line therapies may be safe in pregnancy. Contraindicated therapies include syk inhibitors, vinca alkaloids, mycophenolate mofetil, cyclophosphamide and danazol. Limited case series report safe administration of the thrombopoietin receptor agonists (TPORAs) without adverse fetal outcomes. While the majority of neonates are unaffected, neonatal platelet counts can decline in the first days after delivery and may require therapy. Maternal treatment and platelet count do not appear to predict the risk of neonatal thrombocytopenia; the strongest predictor is a previous sibling’s history. ITP is not a contraindication for pregnancy; women with a history of ITP should not be discouraged from becoming pregnant as their ITP can be safely managed with close monitoring and multidisciplinary coordination with obstetrics and pediatrics.

… for thrombopoietin receptor agonists (eltrombopag and romiplostim) is limited in pregnancy, … Thrombocytopenia is a relatively common hematological abnormality in pregnancy. The …