难治性免疫性血小板减少症经过一、二线药物治疗均无效,或脾切除无效/术后复发。难治性患者血小板计数低,出血风险高,常规治疗手段效果有限,其机制尚不清楚。本文从T细胞的通路、异常活化及受体三方面展开,通路方面我们发现T细胞的特异...难治性免疫性血小板减少症经过一、二线药物治疗均无效,或脾切除无效/术后复发。难治性患者血小板计数低,出血风险高,常规治疗手段效果有限,其机制尚不清楚。本文从T细胞的通路、异常活化及受体三方面展开,通路方面我们发现T细胞的特异性克隆导致细胞毒性增加,并触发血小板活化和凋亡,甲基化诱导一些敏感基因的表达,导致免疫的失衡,使得基因下游的细胞因子释放异常,从而影响血小板的增殖及凋亡,MDSC (髓源性抑制细胞)会释放一些抑制性配体阻碍T细胞的增殖,挽救LKB1-AMPK信号通路分子和抑制性细胞因子的表达缺陷,增强了T细胞增殖。T细胞异常活化导致一些细胞因子的持续表达或相对消除,致使对一线治疗无反应。受体方面发现CD8+ T细胞毒性高的人群中Neu1易位程度高,抗GPIb/IX抗体似乎会导致更多的血小板凋亡,抑制其活性,血小板的唾液酸化会减少。通过这三方面来总结导致难治性ITP可能发生的机制,为诊断难治性ITP的新型标志物或为治疗靶点提供更多的信息。Refractory immune thrombocytopenia is ineffective after first- and second-line drug therapy, or splenectomy is ineffective/relapsed after surgery. Refractory patients have low platelet counts, high bleeding risk, and limited response to conventional treatments, and the mechanism is unclear. This article focuses on the pathways, abnormal activation, and receptors of T cells. In this paper, we found that the specific cloning of T cells leads to increased cytotoxicity and triggers platelet activation and apoptosis, methylation induces the expression of some sensitive genes, resulting in an imbalance of immunity, which makes the cytokine release downstream of genes abnormal, thereby affecting the proliferation and apoptosis of platelets, and MDSCs (myeloid-derived suppressor cells) will release some inhibitory ligands to hinder the proliferation of T cells and rescue LKB1-AMPK Defective expression of signaling pathway molecules and inhibitory cytokines enhances T cell proliferation. Aberrant T cell activation results in sustained expression or relative elimination of some cytokines, resulting in non-response to first-line therapy. In terms of receptors, it was found that the degree of Neu1 translocation was high in people with high CD8+ T cytotoxicity, and anti-GPIb/IX antibodies appeared to cause more platelet apoptosis, inhibit their activity, and reduce platelet sialylation. Through these three aspects, we summarize the mechanisms that may lead to the occurrence of refractory ITP, and provide more information for new markers for diagnosing refractory ITP or for therapeutic targets.展开更多
免疫性血小板减少症(Immune Thrombocytopenia, ITP)是犬常见的一种自身免疫性凝血疾病,目前兽医学对ITP的诊断主要是排除法。治疗主要以糖皮质激素为主,并联合免疫抑制剂使用,常用药物包括皮质类固醇、静脉注射免疫球蛋白,静脉注射长...免疫性血小板减少症(Immune Thrombocytopenia, ITP)是犬常见的一种自身免疫性凝血疾病,目前兽医学对ITP的诊断主要是排除法。治疗主要以糖皮质激素为主,并联合免疫抑制剂使用,常用药物包括皮质类固醇、静脉注射免疫球蛋白,静脉注射长春新碱、硫唑嘌呤、环孢素、霉酚酸酯等,在复发性病例会考虑脾切除等。但针对顽固性、难治性的ITP,上述治疗通常无法改善病情,患犬会因为血小板减少导致进行性的血液丢失,需要通过持续输注全血来维持生命,最终面临死亡。本报告旨在探讨犬ITP的新型治疗手段,尤其是类似本文4例对常规一、二线治疗无反应的难治性ITP。在本报告中,将新型的治疗药物血小板生成素受体激动剂罗米司亭,用于4例经多种糖皮质激素和不同免疫抑制剂联合给药均无改善的难治性ITP患犬,皮下注射罗米司亭后3天血小板数量开始恢复,并随时间的持续增长保持稳定,达到临床缓解,且无临床不良反应。实践证明,使用血小板生成素受体激动剂罗司亭治疗高度敏感且安全。Immune thrombocytopenia (ITP) is a common autoimmune coagulation disease in dogs. At present, the diagnosis of ITP is mainly exclusion method in veterinary medicine. Treatment is mainly based on glucocorticoids and combined with immunosuppressants. Commonly used drugs include corticosteroids, intravenous immunoglobulin, intravenous vincristine, azathioprine, cyclosporine, mycophenolate mofetil, etc., splenectomy will be considered in recurrent cases. However, for intractable and refractory ITP, when the above treatment is ineffective, because of the progressive blood loss caused by thrombocytopenia, the affected dog needs multiple blood infusions to maintain life, and eventually faces death. The purpose of this report is to discuss the new treatment for canine ITP, especially the 4 cases of refractory ITP that did not respond to conventional first-line and second-line treatment. In this report, Romiplostim, a new therapeutic drug thrombopoietin receptor agonist, was used in 4 dogs with refractory ITP who did not improve after the combined administration of multiple glucocorticoids and different immunosuppressants. The number of platelets began to recover 3 days after the subcutaneous injection of Romiplostim, and remained stable over time, achieving clinical remission, and no clinical adverse reactions. Practice has proved that the use of thrombopoietin receptor agonist Romiplostim is highly sensitive and safe.展开更多
文摘难治性免疫性血小板减少症经过一、二线药物治疗均无效,或脾切除无效/术后复发。难治性患者血小板计数低,出血风险高,常规治疗手段效果有限,其机制尚不清楚。本文从T细胞的通路、异常活化及受体三方面展开,通路方面我们发现T细胞的特异性克隆导致细胞毒性增加,并触发血小板活化和凋亡,甲基化诱导一些敏感基因的表达,导致免疫的失衡,使得基因下游的细胞因子释放异常,从而影响血小板的增殖及凋亡,MDSC (髓源性抑制细胞)会释放一些抑制性配体阻碍T细胞的增殖,挽救LKB1-AMPK信号通路分子和抑制性细胞因子的表达缺陷,增强了T细胞增殖。T细胞异常活化导致一些细胞因子的持续表达或相对消除,致使对一线治疗无反应。受体方面发现CD8+ T细胞毒性高的人群中Neu1易位程度高,抗GPIb/IX抗体似乎会导致更多的血小板凋亡,抑制其活性,血小板的唾液酸化会减少。通过这三方面来总结导致难治性ITP可能发生的机制,为诊断难治性ITP的新型标志物或为治疗靶点提供更多的信息。Refractory immune thrombocytopenia is ineffective after first- and second-line drug therapy, or splenectomy is ineffective/relapsed after surgery. Refractory patients have low platelet counts, high bleeding risk, and limited response to conventional treatments, and the mechanism is unclear. This article focuses on the pathways, abnormal activation, and receptors of T cells. In this paper, we found that the specific cloning of T cells leads to increased cytotoxicity and triggers platelet activation and apoptosis, methylation induces the expression of some sensitive genes, resulting in an imbalance of immunity, which makes the cytokine release downstream of genes abnormal, thereby affecting the proliferation and apoptosis of platelets, and MDSCs (myeloid-derived suppressor cells) will release some inhibitory ligands to hinder the proliferation of T cells and rescue LKB1-AMPK Defective expression of signaling pathway molecules and inhibitory cytokines enhances T cell proliferation. Aberrant T cell activation results in sustained expression or relative elimination of some cytokines, resulting in non-response to first-line therapy. In terms of receptors, it was found that the degree of Neu1 translocation was high in people with high CD8+ T cytotoxicity, and anti-GPIb/IX antibodies appeared to cause more platelet apoptosis, inhibit their activity, and reduce platelet sialylation. Through these three aspects, we summarize the mechanisms that may lead to the occurrence of refractory ITP, and provide more information for new markers for diagnosing refractory ITP or for therapeutic targets.
文摘免疫性血小板减少症(Immune Thrombocytopenia, ITP)是犬常见的一种自身免疫性凝血疾病,目前兽医学对ITP的诊断主要是排除法。治疗主要以糖皮质激素为主,并联合免疫抑制剂使用,常用药物包括皮质类固醇、静脉注射免疫球蛋白,静脉注射长春新碱、硫唑嘌呤、环孢素、霉酚酸酯等,在复发性病例会考虑脾切除等。但针对顽固性、难治性的ITP,上述治疗通常无法改善病情,患犬会因为血小板减少导致进行性的血液丢失,需要通过持续输注全血来维持生命,最终面临死亡。本报告旨在探讨犬ITP的新型治疗手段,尤其是类似本文4例对常规一、二线治疗无反应的难治性ITP。在本报告中,将新型的治疗药物血小板生成素受体激动剂罗米司亭,用于4例经多种糖皮质激素和不同免疫抑制剂联合给药均无改善的难治性ITP患犬,皮下注射罗米司亭后3天血小板数量开始恢复,并随时间的持续增长保持稳定,达到临床缓解,且无临床不良反应。实践证明,使用血小板生成素受体激动剂罗司亭治疗高度敏感且安全。Immune thrombocytopenia (ITP) is a common autoimmune coagulation disease in dogs. At present, the diagnosis of ITP is mainly exclusion method in veterinary medicine. Treatment is mainly based on glucocorticoids and combined with immunosuppressants. Commonly used drugs include corticosteroids, intravenous immunoglobulin, intravenous vincristine, azathioprine, cyclosporine, mycophenolate mofetil, etc., splenectomy will be considered in recurrent cases. However, for intractable and refractory ITP, when the above treatment is ineffective, because of the progressive blood loss caused by thrombocytopenia, the affected dog needs multiple blood infusions to maintain life, and eventually faces death. The purpose of this report is to discuss the new treatment for canine ITP, especially the 4 cases of refractory ITP that did not respond to conventional first-line and second-line treatment. In this report, Romiplostim, a new therapeutic drug thrombopoietin receptor agonist, was used in 4 dogs with refractory ITP who did not improve after the combined administration of multiple glucocorticoids and different immunosuppressants. The number of platelets began to recover 3 days after the subcutaneous injection of Romiplostim, and remained stable over time, achieving clinical remission, and no clinical adverse reactions. Practice has proved that the use of thrombopoietin receptor agonist Romiplostim is highly sensitive and safe.
