口服抗凝剂治疗以新生儿暴发性紫癜或颅内出血为首发表现的遗传性复合杂合突变的重度蛋白C缺乏症2例病例报告并文献复习

Oral anticoagulant treatment of severe protein C deficiency with a hereditary compound heterozygous mutation with neonatal fulminant purpura or intracranial hemorrhage as the first manifestation: Two cases report and literature review

背景 既往国内报道的重度遗传性蛋白C缺乏症(PCD)患儿大多放弃救治而死亡。目的 探索口服抗凝剂对重度PCD患儿的长期救治效果。设计病例报告。方法 报道并分析2例新生儿期起病的遗传性复合杂合突变的重度PCD患儿的诊断、治疗及预后,检索PubMed、中国知网和万方数据库,行文献复习。主要结局指标血栓或出血缓解。结果 1例首发表现为新生儿暴发性紫癜(PF);1例因存在继发性慢性DIC,以新生儿颅内出血、肺出血为首发表现。2例经基因测序均明确蛋白C(PROC)基因复合杂合突变。每日应用新鲜冷冻血浆及低分子肝素抗凝获得初步缓解后,分别序贯口服维生素K拮抗剂华法林或直接口服抗凝剂利伐沙班作为长期治疗,预防血栓及出血事件,随访3~6年,2例均存活至今,生存质量尚好,且无明显不良反应。结论 重度遗传性PCD可以新生儿PF、颅内出血和肺出血为首发表现,应改变观念积极救治;华法林和利伐沙班等口服抗凝剂可以作为长期维持治疗时安全有效的选择,改善预后。

Background Given the poor prognosis of severe hereditary protein C deficiency(PCD), most of the children with severe PCD reported in China gave up treatment and died. Objective We aimed to explore the long-term therapeutic effect of oral anticoagulants on children with PCD. Design Case report. Methods We reported 2 cases with severe hereditary PCD, both having compound heterozygous protein C gene(PROC) mutations. PubMed, CNKI and Wanfang databases were consulted from 1981 to 2021 to find out other cases reported in China. And all the cases were analyzed together on diagnosis, treatment and prognosis. Main outcome measures Thrombotic or bleeding relief. Results Case 1 first manifested as fulminant purpura, while case 2 first presented intracranial hemorrhage and pulmonary hemorrhage due to the chronic disseminated intravascular coagulation(DIC). Gene sequencing on both cases showed compound heterozygous mutation on PROC gene. Daily fresh frozen plasma(FFP) infusion and low molecular heparin(LWMH) worked as emergency treatment. Vitamin K antagonist(VKA) warfarin and direct oral anticoagulant(DOAC) rivaroxaban were used sequentially as long-term treatment to prevent thrombotic events, and hemorrhage. Both cases survived through the 3-6 years of follow-up without obvious side effects.Conclusion Severe hereditary PCD can have neonate fulminant purpura, as well as intracranial hemorrhage and pulmonary hemorrhage as the initial manifestations. Doctors and parents should choose active treatment instead of giving up. Warfarin and rivaroxaban could be considered as safe and effective long-term alternatives for patients with severe PCD in infancy which could also improve prognosis.