重组人凝血因子Ⅷ对α-凝血酶生成活性的影响  

The Effect of Recombinant Human Coagulation FactorⅧon Alphathrombin Generation Activity

作　　者：宋春雷 丁亚凌 侯仰帅 李德款 伍立恒 曾金杰 梁洪 SONG Chunlei;DING Yaling;HOU Yangshuai;LI Dekuan;WU Liheng;ZENG Jinjie;LIANG Hong(Chengdu Rongsheng Pharmaceuticals Co.Ltd.,Chengdu 610041,China;Beijing Tiantan Biological Products Co.Ltd.,Beijing 100024,China)

机构地区：[1]成都蓉生药业有限责任公司,四川成都610041 [2]北京天坛生物制品有限公司,北京100024

出　　处：《药物生物技术》2024年第3期241-244,共4页Pharmaceutical Biotechnology

基　　金：成都市科学技术局重大科技创新项目(No.2019-YF08-00308-GX)。

摘　　要：A型血友病是最常见的遗传性出血疾病,其共同的特征是活性凝血酶生成障碍,凝血时间延长,临床上主要表现为凝血因子Ⅷ(FⅧ)质或量的异常,以关节、肌肉、内脏和深部组织自发性或轻微外伤后出血难以停止为特征,常在儿童期起病,反复关节出血可导致患者逐渐出现关节活动障碍而致残。男性人群中,A型血友病的发病率约为1/5000,而女性血友病患者极其罕见。我国血友病的患病率为2.73/100000人口,其中A型血友病占80%~85%。实验旨在探究重组人凝血因子Ⅷ(rhFⅧ)对下游凝血途经的激活能力,并与已上市同类产品进行比较。以缺凝血因子Ⅷ血浆为实验组样本,标准血浆为对照组,利用缓冲液将各个产品稀释至1、5和10 IU/mL,得到3个FⅧ活性工作液,所制备FⅧ工作液再用缺凝血因子Ⅷ血浆(模拟血友病甲样本)稀释10倍,制成0、0.1、0.5、1 IU/mL 4种不同活性FⅧ血浆样本,利用凝血酶生成分析仪分别检测rhFⅧ、Advate和血源FⅧ在不同浓度条件下,对α-凝血酶生成速度及生成潜力的影响。与Advate、血源FⅧ相比,rhFⅧ具有相同的促α-凝血酶生成效果;且α-凝血酶生成的峰高随FⅧ浓度的增加而呈上升趋势;达峰时间随FⅧ浓度的增加而呈下降趋势;α-凝血酶生成曲线下积分面积随FⅧ浓度增加而增加。rhFⅧ与市售重组及血源性FⅧ产品相比,在体外具有相同的促α-凝血酶生成活性,具备良好的成药性,未来有望在国内获批上市。Haemophilia A is the most common inherited bleeding disorder and is commonly characterised by impaired generation of active thromboplastin and prolonged clotting time.The main clinical manifestations are qualitative or quantitative abnormalities of coagulation factorⅧ(FⅧ).Clinical manifestations are characterised by spontaneous bleeding in joints,muscles,internal organs and deep tissues or bleeding that is difficult to stop after minor trauma,often starting in childhood.Repeated bleeding in joints can lead to gradual joint mobility disorders and disability.The incidence of haemophilia A in the male population is about 1 in 5000,while haemophilia A in women is extremely rare.The prevalence of haemophilia in China is 2.73/100000 population,of which haemophilia A accounts for 80%~85%.The aim of this study was to investigate the ability of recombinant human coagulation factorⅧ(rhFⅧ)to activate downstream coagulation pathways and to compare it with marketed analogues.Using coagulation factorⅧdeficient plasma as the experimental group sample and standard plasma as the control group,three FⅧactive working solutions were obtained by diluting each product to 1,5 and 10 IU/mL using buffer,and then the prepared FⅧworking solutions were diluted 10-fold with coagulation factorⅧdeficient plasma(simulated haemophilia A samples)to make four different FⅧworking solutions of 0,0.1,0.5 and 1 IU/mL activity FⅧplasma samples,and the effects of rhFⅧ,Advate and blood-derived FⅧon the rate ofα-thrombin generation and the potential of generation under different concentration conditions were detected by using a thrombin generation analyser,respectively.rhFⅧhad the same effect of promotingα-thrombin generation compared with Advate and blood source FⅧ,and the peak height ofα-thrombin generation showed an increasing trend with the increase of FⅧconcentration;the peak time showed a decreasing trend with the increase of FⅧconcentration in FⅧ;and the integral area under theα-thrombin generation curve increa

关 键 词：A型血友病 重组人凝血因子Ⅷ α-凝血酶 生成速度 凝血酶活性 凝血功能 

分 类 号：R554.1[医药卫生—血液循环系统疾病]