摘要
目的探讨难治性重度持续性化疗相关无巨核细胞性血小板减少症(ATT)患者的临床特征、治疗策略,并进行相关文献复习。方法选择2023年10月28日中国医学科学院血液病医院贫血诊疗中心收治的1例60岁男性难治性重度持续性化疗相关AAT患者(患者1)为研究对象。采用回顾性分析方法,对其病史、临床特征、实验室及辅助检查结果,以及诊治过程进行分析。对患者1的随访截至2025年1月18日。本研究以"无巨核细胞性血小板减少症""血小板生成素受体激动剂""海曲泊帕""艾曲泊帕""阿伐曲泊帕""amegakaryocytic thrombocytopenia""thrombopoietin receptor agonist""TPO-RA""hetrombopag""eltrombopag""avatrombopag"为中、英文关键词,在中国知网数据库、万方数据知识服务平台及PubMed数据库中,检索本研究病例相关文献,并且对文献报道的ATT患者的临床特点、诊断、治疗及预后进行分析和总结。文献检索时间设定为1980年1月1日至2025年1月1日。本研究符合2013年修订的《世界医学协会赫尔辛基宣言》要求,并且征得受试者及其家属知情同意。结果①患者1因"结肠癌化疗后血小板计数持续性减少4个月"入院。病史采集:患者1于1年前因乙状结肠中低分化腺癌行乙状结肠癌根治术+淋巴结清扫,术后共进行8个疗程卡培他滨+奥沙利铂方案化疗。化疗结束后患者1血小板计数下降并呈进行性加重,应用重组人血小板生成素(rhTPO)治疗无效,间断输注单采血小板治疗。②入院后,患者1血常规检查结果示,血小板计数为31×10^(9)/L(最低降至6×10^(9)/L),淋巴细胞百分比为41.5%。骨髓细胞形态学检查结果示,骨髓有核细胞增生活跃(-),全片未见巨核细胞。免疫组织化学染色结果示,全片见正常巨核细胞1个。骨髓病理学检查结果示巨核细胞偶见。③根据临床特征、血常规检查、骨髓细胞形态学检查和免疫组织化学检查结果,患者1被诊断为ATT,肿瘤化疗相关。患者1接受海曲泊帕促血小板生成,起始剂量为10 mg/d,逐步增加剂量至12.5 mg/d。同时,患者1采取联合免疫抑制方案治疗,即小剂量环孢素(50~75 mg/次,每2 d应用1次)与左旋咪唑(50 mg/次,每2 d应用3次),联合应用达那唑促进造血,剂量为100 mg/次,3次/d。此外,患者1平均每周输注单采血小板1 U,8周后患者血小板计数可稳定在约10×10^(9)/L。随后将海曲泊帕剂量增加至15 mg/d,持续应用6周,但是血小板计数仍无明显改善。遂更换药物为阿伐曲泊帕,剂量为20 mg/次,3次/d。用药第5天,患者1血小板计数即升高至18×10^(9)/L,用药3周时血小板计数恢复正常(100×10^(9)/L)。患者1血小板计数升至200×10^(9)/L后逐步减低阿伐曲泊帕剂量至20 mg/d维持治疗,血常规检查结果持续正常14^(+)个月。④根据本研究设定的文献检索策略,共纳入6篇文献,报道8例ATT患者(患者2~9),加上本例患者共9例患者被纳入研究。9例ATT患者中,2例为化疗相关ATT,4例为免疫抑制剂相关AAT,3例为自身免疫性疾病相关AAT;患者的主要临床症状为严重血小板计数减少,骨髓巨核细胞减少或缺如。9例患者均接受TPO受体激动剂(TPO-RA)或联合免疫抑制剂的治疗方案,在治疗后血小板计数获得显著改善,并且疗效能够维持。9例患者中最长随访时间为36个月,除1例患者死于肺癌恶化,其余患者均未复发。结论对于ATT患者应注意鉴别诊断,治疗无效时应及时更换药物。AAT的首选治疗方案为环孢素±TPO-RA,对于难治性重度持续性AAT使用海曲泊帕、艾曲泊帕治疗无效时,阿伐曲泊帕或者阿伐曲泊帕联合环孢素可作为进一步治疗方案,以改善患者疗效及预后。
Objective To investigate clinical characteristics and treatment strategies of patients with refractory severe persistent chemotherapy-induced amegakaryocytic thrombocytopenia(AAT),and review related literature.Methods On October 28,2023,a case of 60-year-old male patient(patient 1)with refractory severe persistent chemotherapy-induced AAT was enrolled from Anemia Diagnosis and Treatment Center,Blood Diseases Hospital,Chinese Academy of Medical Sciences.A retrospective analysis was conducted on his medical history,clinical characteristics,laboratory and auxiliary examination results,as well as diagnosis and treatment process.Follow-up for patient 1 was completed as of January 18,2025.China National Knowledge Infrastructure database,Wanfang Data Knowledge Service Platform,and PubMed databases were searched by keywords"amegakaryocytic thrombocytopenia""thrombopoietin receptor agonist""hetrombopag""eltrombopag""avatrombopag""TPO-RA"in Chinese and English for literature related to this case.Clinical characteristics,diagnosis,treatment,and prognosis of AAT patients reported in the literature were analyzed and summarized.Time for literature retrieval was set from January 1,1980 to January 1,2025.Procedures followed in this study were in line with requirements of World Medical Association Declaration of Helsinki revised in 2013,and informed consent of clinical research was obtained from patient 1 and his family.Results ①Patient 1 was admitted due to"persistent thrombocytopenia for 4 months after colon cancer chemotherapy".Medical history:patient 1 underwent radical resection of sigmoid colon adenocarcinoma with lymph node dissection 1 year ago,and received 8 cycles of capecitabine+oxaliplatin regimen chemotherapy.Platelet count decreased progressively after chemotherapy,patient 1 was unresponsive to recombinant human thrombopoietin(rhTPO)and required intermittent apheresis platelet transfusions.②After admission,blood routine examination results showed platelet count of 31×10^(9)/L(dropped to a minimum of 6×10^(9)/L),lymphocyte percentage of 41.5%.Bone marrow morphological examinations result showed hypocellular marrow,and no megakaryocytes observed.Immunohistochemistry result showed 1 normal megakaryocyte per slide.Bone marrow pathological examination results showed rare megakaryocytes.③Based on clinical features,blood routine examination,bone marrow cell morphology examination and immunohistochemical examination results,patient 1 was diagnosed with ATT related to tumor chemotherapy.Patient 1 received hetrombopag to promote platelet production.Initial dose was 10 mg/d,and dose was gradually increased to 12.5 mg/d.At the same time,patient 1 was given a combined immunosuppressive treatment regimen,which was low-dose cyclosporine(50-75 mg/time,once every 2 d)and levamisole(50 mg/time,3 times every 2 d),combined with danazole to promote hematopoiesis,at a dose of 100 mg/time,3 times a day.In addition,patient 1 received an average of 1 U of apheresis platelets per week.After 8 weeks,patient 1′s platelet count could be stabilized at approximately 10×10^(9)/L.Subsequently,dose of hetrombopag was increased to 15 mg/d and continued for 6 weeks.However,there was still no significant improvement in platelet count.Therefore,hetrombopag was changed to avatrombopag,with a dose of 20 mg/time,3 times a day.On the 5th day of medication,platelet count of patient 1 increased to 18×10^(9)/L.After 3 weeks of medication,platelet count returned to normal(100×10^(9)/L).After platelet count of patient 1 rose to 200×10^(9)/L,dose of avatracopag was gradually reduced to 20 mg/d for maintenance treatment.Results of the blood routine test remained normal for 14^(+)months.④According to literature search strategy set in this study,6 articles were selected,collectively reporting 8 cases of ATT(numbered as patient 2-9).There were 9 cases of ATT patients,including patient 1.Among the 9 ATT patients,2 cases were chemotherapy related ATT,4 cases were immunosuppressants related AAT,and 3 cases were autoimmune diseases related AAT.Main clinical symptoms were severe thrombocytopenia and a reduction or absence of megakaryocytes in bone marrow.All 9 patients received treatment regimens of thrombopoietin receptor agonist(TPO-RA)or combined immunosuppressants,and their platelet counts improved significantly after treatment,and therapeutic effect could be maintained.Among 9 patients,the longest follow-up period was 36 months.Except for 1 patient who died of lung cancer deterioration,the rest of patients did not have recurrence.Conclusions For patients with ATT,attention should be paid to differential diagnosis.When treatment is ineffective,drugs should be changed in time.Preferred treatment regimen for AAT is cyclosporine±TPO-RA.For refractory,severe and persistent AAT,when hetrombopag,eltrombopag treatment is ineffective,avatrombopag or avatrombopag combined with cyclosporine can be selected as a further treatment to improve the therapeutic effect and prognosis of patients.
作者
刘文昊
任翔
Paudel Pratiksha
郑以州
葛美丽
Liu Wenhao;Ren Xiang;Paudel Pratiksha;Zheng Yizhou;Ge Meili(State Key Laboratory of Experimental Hematology,National Clinical Research Center for Blood Diseases,Haihe Laboratory of Cell Ecosystem,Institute of Hematology&Blood Diseases Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,China Tianjin Institutes of Health Science,Tianjin 300020,China;International Medical School,Tianjin Medical University,Tianjin 300070,China)
出处
《国际输血及血液学杂志》
2025年第2期117-127,共11页
International Journal of Blood Transfusion and Hematology
