Diagnosis and Management of an Infant with Hereditary Protein C Deficiency with Compound Mutation of PROC Gene
遗传性蛋白C缺乏症(hereditary protein C deficiency，HPCD)主要表现为罕见的新生儿期暴发性紫癜，疾病进展迅速，死亡率高，诊治困难，早期识别和正确诊治可显著改善预后。本文报道1例PROC基因复合杂合突变所致的新生儿HPCD，患儿出生后24 h内即出现反复皮肤紫癜，6月龄前辗转就诊于国内多家医院，未明确诊断。我院就诊期间查患儿凝血功能异常，蛋白C水平极低，通过静脉输注新鲜冰冻血浆及长期口服抗凝药物治疗，患儿病情控制良好，该病例为国内首例成功救治的最小年龄HPCD病例。儿科医师在临床实践中应提高对该病的早期识别能力；新鲜冰冻血浆联合口服抗凝药物治疗HPCD效果确切，在无蛋白C浓缩物的情况下，临床上可考虑该治疗方案。Abstract:
Hereditary protein C deficiency (HPCD) is a rare hereditary thrombophilia leading to thromboembolic events during the neonatal period. We reported a case of Chinese newborn with HPCD, presenting with purpura fulminans. She was diagnosed as HPCD at 6 months old. Coagulation studies showed prolonged PT and APTT, low fibrinogen and high D-dimer levels. The circulating protein C level was only 1%. She was originally misdiagnosed as having sepsis but not properly diagnosed and treated until admission to our hospital at the age of 6 months. Daily infusion of fresh frozen plasma was used as the initial treatment since protein C concentrates were not available. Warfarin was used as a long-term treatment to prevent thrombotic events, with regular international normalized ratio and D-dimer level being monitored. Genetic analysis showed compound heterozygous mutation. Early diagnosis is very important for prompt life-saving treatment. This was the youngest surviving patient reported in China.HPCD is rare in China. Recognition of the special skin lesions is important. Fresh frozen plasma and anticoagulant combined with oral warfarin were used with good effects in the treatment, which could be an alternative when protein C concentrate is not easily available in the developing countries.
- hereditary protein C deficiency /
- neonates /
表 1 不同治疗时期患儿凝血功能检查结果
项目 4月龄 6月龄 输注血浆前 输注血浆后 参考值范围 血小板(×109/L) 280 300 280 276 100~350 PT(s) 21.6 13.8 19.3 12.7 13.5~16.4 APTT(s) 91.6 36.3 39.9 36.8 29.5~42.2 FBG(g/L) 0.18 0.77 0.63 2.9 2.83~4.01 D-二聚体(mg/L) 28.80 4.80 27.37 0.60 0~0.55 蛋白C活性(%) ＜1 1 8 60~140 PT：凝血酶原时间；APTT：活化部分凝血活酶时间；FBG：纤维蛋白原
 Ogiwara K, Nogami K, Mizumachi K, et al. Hemostatic assessment of combined anticoagulant therapy using warfarin and prothrombin complex concentrates in a case of severe protein C deficiency[J]. Int J Hematol, 2019, 109: 650-656. doi: 10.1007/s12185-019-02645-7  Wu YT, Yue F, Wang M, et al. Hereditary protein C deficiency caused by compound heterozygous mutants in two independent Chinese families[J]. Pathology, 2014, 46: 630-635. http://www.ncbi.nlm.nih.gov/pubmed/25393254  Dreyfus M, Magny JF, Bridey F, et al. Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate[J]. N Engl J Med, 1991, 325: 1565-1568. doi: 10.1056/NEJM199111283252207  Poort SR, Pabinger-Fasching I, Mannhalter C, et al. Twelve novel and two recurrent mutations in 14 Austrian families with hereditary protein C deficiency[J]. Blood Coagul Fibrinolysis, 1993, 4: 273-280. doi: 10.1097/00001721-199304000-00009  Griffin JH, Evatt B, Zimmerman TS, et al. Deficiency of protein C in congenital thrombotic disease[J]. J Clin Invest, 1981, 68: 1370-1373. doi: 10.1172/JCI110385  Karpatkin M, Mannuccio Mannucci P, Bhogal M, et al. Low protein C in the neonatal period[J]. Br J Haematol, 1986, 62: 137-142. doi: 10.1111/j.1365-2141.1986.tb02909.x  Reitsma PH. Protein C deficiency: from gene defects to disease[J]. Thromb Haemost, 1997, 78: 344-350. doi: 10.1055/s-0038-1657550  Tripodi A, Salerno F, Chantarangkul V, et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests[J]. Hepatology, 2005, 41: 553-558. doi: 10.1002/hep.20569  Mannucci PM, Vigano S. Deficiencies of protein C, an inhibitor of blood coagulation[J]. Lancet, 1982, 2: 463-467. http://www.ncbi.nlm.nih.gov/pubmed/6125639  Olivieri M, Bidlingmaier C, Schetzeck S, et al. Arterial thrombosis in homozygous antithrombin deficiency[J]. Hamostaseologie, 2012, 32: s79-s82. doi: 10.1055/s-0037-1619781  Tridapalli E, Stella M, Capretti MG, et al. Neonatal arterial iliac thrombosis in type-1 protein C deficiency: a case report[J]. Ital J Pediatr, 2010, 36: 23. doi: 10.1186/1824-7288-36-23  Baothman AA, AlSobhi E, Khayat HA, et al. A delayed presentation of homozygous protein C deficiency in a series of children: a report on two molecular defects[J]. Clin Case Rep, 2017, 5: 315-320 doi: 10.1002/ccr3.699  Inoue H, Terachi SI, Uchiumi T, et al. The clinical presentation and genotype of protein C deficiency with double mutations of the protein C gene[J]. Pediatr Blood Cancer, 2017, 64. doi: 10.1002/pbc.26404.  杨凤丽, 李浩, 陈琴, 等. 新生儿遗传性蛋白C缺乏症所致暴发性紫癜一例[J]. 中国新生儿科杂志, 2015, 30: 230-231. https://www.cnki.com.cn/Article/CJFDTOTAL-GYYX202020033.htm  Kizilocak H, Ozdemir N, Dikme G, et al. Homozygous protein C deficiency presenting as neonatal purpura fulminans: management with fresh frozen plasma, low molecular weight heparin and protein C concentrate[J]. J Thromb Thrombolysis, 2018, 45: 315-318. doi: 10.1007/s11239-017-1606-x  Kroiss S, Albisetti M. Use of human protein C concentrates in the treatment of patients with severe congenital protein C deficiency[J]. Biologics, 2010, 4: 51-60. http://www.ams.org/mathscinet-getitem?mr=2725421  Manco-Johnson MJ, Bomgaars L, Palascak J, et al. Efficacy and safety of protein C concentrate to treat purpura fulminans and thromboembolic events in severe congenital protein C deficiency[J]. Thromb Haemost, 2016, 116: 58-68. doi: 10.1160/TH15-10-0786  Lee MJ, Kim KM, Kim JS, et al. Long-term survival of a child with homozygous protein C deficiency successfully treated with living donor liver transplantation[J]. Pediatr Transplant, 2009, 13: 251-254. doi: 10.1111/j.1399-3046.2008.00972.x