凝血Ⅶ因子在颅脑创伤相关性凝血功能障碍的发生和治疗中的作用

发布时间：2018-03-29 07:02

本文选题：凝血　切入点：因子　出处：《复旦大学》2013年博士论文

【摘要】：[第一部分] 研究目的：通过监测急性期单纯性中重度颅脑损伤患者血浆凝血VII因子(FVII)水平的变化,了解FVII活性的变化与凝血功能障碍以及颅脑损伤后进展性出血的关系。研究方法： 2010至2012年期间,对急诊入院的单纯型中重度颅脑创伤患者进行筛选,符合入选标准的患者记录一般情况,并进行伤后24小时内静脉血标本采集,使用ELISA试剂盒检测血浆FVIIa活性变化,同时记录包括凝血酶原时间(PT)、部分活化凝血酶原时间(aPTT),凝血酶时间,纤维蛋白原(FIB),D—二聚体,和国际标准化比率(INR)在内的凝血功能指标。颅脑创伤相关的凝血病定义为血小板减少(120000/mm3),或INR上升(1.2),或者PT延长(40秒)。根据影像学指标判断颅内出血病灶情况。通过Logistic回归模型分析凝血功能异常以及进展性出血与颅脑创伤的关系。研究结果：共81例患者纳入研究,其中发生凝血功能障碍者44例(54.3%)FVII的活性在伴有以及不伴有凝血功能障碍的患者中分别为85.69±34.88%和99.57%±29.37%,两者差别显著(p=0.041)。单纯性颅脑创伤患者FVII活性77.5%产生凝血功能障碍的风险显著增加(OR=5.52,95%CI1.82～16.68,p=0.03)。在存在进展性出血与无进展性出血的患者中,FVII的活性分别为70.76±18.21%和105.76±32.27%,两者差别显著(p0.001)。渐进Logistic回归分析显示FVII77.5%是出血病灶进展的独立危险因素(0R=4.53,95%CI1.62～12.67,p=0.004)。所有患者的死亡率为7.4%(n=6)。死亡患者中FVII的活性为91.44±47.19%,略低于生存患者的92.01±32.04%,但差异无统计学意义。研究结论：在急性单纯型中重度颅脑创伤患者中,FVII活性与凝血功能状态密切相关,首次发现FVII活性77.5%是发生凝血功能障碍和发生进展性出血的独立危险因素。[第二部分] 研究目的：比较发生凝血功能障碍与凝血功能正常组患者在6个FVII多态性位点的差异,了解FVII基因多态性与凝血功能障碍的关系。研究方法：采取前瞻性、病例-对照研究,筛选2011年3月至2012年12月期间的急性单纯型中重度颅脑创伤患者。采集入选患者的一般情况、诊疗信息以及预后信息。急性期采集患者外周静脉血,用血液基因组DNA提取试剂盒提取外周血DNA,取2ul电泳(2%琼脂糖凝胶,120V,20分钟)检测提取DNA的量,紫外分光光度仪检测DNA浓度以及纯度。采取限制性片段长度多态性—聚合酶链反应(PCR-RFLP)技术检测方法检测FVII基因-323P0/P10、R353Q、-401G/T、-402G/A、-670A/C和IVS7位点的基因表型。探讨基因多态性与单纯型颅脑创伤后凝血功能状态之间的关系。研究结果：共入选91例患者,平均年龄51.67±16.67岁。其中发生凝血功能障碍者20例,凝血功能正常者77例。FVII基因-323P0/P10多态性PCR扩增产物长度为214bp和224bp, R353Q多态性PCR扩增产物长度为239bp,-401G/T和-402G/A多态性PCR扩增产物长度均为467bp,-670A/C多态性PCR扩增产物长度为192bp,IVS7多态性PCR扩增产物长度为443bp和480bp。Hardy-Weinberg遗传平衡检验显示,各多态性位点的基因表型分布均符合Hardy-Weinberg平衡,来自同一群体。比较两组患者的多态性分布情况显示,-402G/A的基因多态性与凝血功能障碍的发病增加有关。随访分析显示-402G/A和-670A/C基因型与患者出院时的GCS较低相关。研究结论： FVII基因多态性的分析显示,国人-402G/A与FVII血浆浓度水平较低以及凝血功能障碍的发生率升高相关。 [第三部分] 研究目的：通过临床前瞻性队列研究,初步探索小剂量重组活化凝血VII因子(rFVIIa20mcg/kg)对颅脑外伤相关性凝血功能障碍的干预以及治疗的作用。研究方法：筛选急诊入院的伴凝血功能障碍的单纯型颅脑创伤患者,将符合入选标准的患者按照纠正凝血功能异常的疗法分为2组,一组在急性期接受早期小剂量rFVIIa(20mcg/kg)治疗,另一组接受常规血制品治疗纠正凝血功能异常。通过72小时的观察,并对患者进行随访,比较两组治疗期间凝血功能指标的恢复情况、不良反应、住院成本和预后的差异。研究结果：共纳入86例患者,其中rFVIIa治疗组27例,常规治疗组59例。统计分析显示,rFVIIa治疗组与常规治疗组的INR纠正程度分别为0.29±0.23和0.11±0.39,两者差异显著(p=0.01)。两组72小时内出现脑梗死病灶几率分别为7.2%(2例)和8.5%(5例),两者无显著差异；两组均未报道深静脉血栓(DVT)的发生。随访30天死亡率在治疗组和对照组分别为22.2%(6例)和32.2%(19例)。两者无显著差异。研究结论：小剂量rFVIIa在急性期可以有效纠正单纯性中重度颅脑创伤患者的凝血功能异常,而不增加深静脉血栓以及急性肺栓塞等血栓栓塞事件的发生。FVII在颅脑创伤相关性凝血功能障碍的发病以及治疗过程中具有重要意义,值得扩大样本例数,开展进一步研究。
[Abstract]:[part I]
The purpose of the study is:
By monitoring the changes of plasma coagulation factor VII (FVII) level in patients with acute moderate severe craniocerebral injury in acute stage, we can understand the relationship between FVII activity and coagulation dysfunction and progressive bleeding after craniocerebral injury.
Research methods:
During the period from 2010 to 2012, the simple type of emergency hospital admission in severe craniocerebral trauma patients were screened, eligible patients were recorded in general, and within 24 hours after injury of venous blood specimens were collected using ELISA kit to detect the changes of plasma FVIIa activity, and records including prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time, fibrinogen (FIB), D - two dimers, and the international normalized ratio (INR), blood coagulation indexes. The definition of craniocerebral trauma associated coagulopathy thrombocytopenia (120000/mm3), or INR (1.2), or increased PT extension (40 seconds) according to the image. Index of judging lesions of intracranial hemorrhage. By Logistic regression model analysis of coagulation abnormalities and progressive hemorrhage and traumatic brain injury.
The results of the study:
A total of 81 patients were included in the study, including 44 cases of blood coagulation dysfunction (54.3%) and the activity of FVII in patients with dysfunction of blood coagulation in patients without were 85.69 + 34.88% and 99.57% + 29.37%, the difference was significant (p=0.041). A significant increase in the risk of patients with FVII craniocerebral injury of 77.5% live coagulopathy (produce OR=5.52,95%CI1.82 - 16.68, p=0.03). In the presence of patients with progressive hemorrhage and non progressive hemorrhage in FVII activity were 70.76 + 18.21% and 105.76 + 32.27%, the difference was significant (p0.001). Logistic progressive regression analysis showed that FVII77.5% is an independent risk factor of hemorrhagic lesion progression (0R=4.53,95%CI1.62 ~ 12.67, p=0.004). The mortality rate was 7.4% (n=6). The death of patients with FVII activity was 91.44 + 47.19%, slightly lower than the survival of 92.01 + 32.04%, but the difference was not statistically significant.
The conclusions are as follows:
In acute in patients with severe craniocerebral trauma, closely related to the activity of FVII and coagulation status, for the first time that FVII 77.5% is activated coagulation dysfunction and progression independent risk factors of bleeding. The second part]
The purpose of the study is:
To compare the difference between 6 FVII polymorphisms loci in patients with coagulation dysfunction and normal coagulation function, and to understand the relationship between FVII polymorphism and coagulation dysfunction.
Research methods:
Take a prospective, case-control study, acute period from March 2011 to December 2012 were in severe craniocerebral trauma patients. Collecting selected the general condition of the patient, the clinical information and prognosis. Collected peripheral venous blood in patients with acute phase blood genomic DNA extraction kit to extract peripheral blood DNA, 2ul electrophoresis (2% agarose gel, 120V, 20 minutes) detection DNA, UV spectrophotometer to detect the DNA concentration and purity. By restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) detection of -323P0/P10, FVII gene detection methods R353Q, -401G/T, -402G/A, -670A/C and IVS7 loci gene phenotype relationship. Between the coagulation status of gene polymorphism and simplex after traumatic brain injury.
The results of the study:
A total of 91 patients were enrolled, the average age of 51.67 + 16.67 years. Among the 20 cases of coagulation dysfunction, coagulation function was normal in 77 cases of.FVII gene -323P0/P10 polymorphism of PCR amplified product length is 214bp and 224bp, R353Q polymorphism of PCR amplified product length is 239bp, -401G/T and -402G/A polymorphism of PCR amplified product length was 467bp -670A/C, polymorphism of PCR amplified product length 192bp, IVS7 polymorphism of PCR amplified product length showed 443bp and 480bp.Hardy-Weinberg balance of genetic testing, gene phenotype distribution of the polymorphic loci were in accordance with the balance of Hardy-Weinberg from the same group. Compared two groups of patients with polymorphism distribution of -402G/A gene polymorphism associated with increased the blood coagulation dysfunction. Follow-up analysis showed that -402G/A and -670A/C genotypes and discharged patients with low GCS.
The conclusions are as follows:
The analysis of FVII gene polymorphism shows that the low level of plasma concentration of -402G/A and FVII and the increase in the incidence of coagulation dysfunction in Chinese people are related.
[third part]
The purpose of the study is:
Based on a prospective cohort study, we explored the intervention and therapeutic effect of low dose recombinant activated coagulation factor VII (rFVIIa20mcg/kg) on coagulopathy associated with craniocerebral trauma.
Research methods:
Simple type of craniocerebral trauma with coagulation dysfunction in patients with emergency admission screening, will meet the inclusion criteria of patients according to correct abnormal blood coagulation therapy were divided into 2 groups, one group received early low-dose rFVIIa in the acute phase (20mcg/kg) treatment, one group received conventional treatment to correct abnormal clotting of blood products through the observation of 72 hours., and follow-up of patients, recovery of adverse reactions were compared between the two groups during the treatment period, blood coagulation index, hospitalization cost differences and prognosis.
The results of the study:
A total of 86 patients, the rFVIIa treatment group 27 cases, 59 cases of conventional treatment group. Statistical analysis showed that INR correct degree of rFVIIa treatment group and routine treatment group were 0.29 + 0.23 and 0.11 + 0.39, the difference is significant (p=0.01). The two groups within 72 hours there were 7.2% (the probability of cerebral lesions 2 cases) and 8.5% (5 cases), there were no significant differences between the two groups were not reported; deep venous thrombosis (DVT). The follow-up of 30 day mortality in the treatment group and control group were 22.2% (6 cases) and 32.2% (19 cases). There was no significant difference between the two.
The conclusions are as follows:
A small dose of rFVIIa in acute stage can effectively correct the severe craniocerebral trauma patients with abnormal coagulation function of simple, without increasing the incidence of.FVII deep vein thrombosis and pulmonary embolism and acute thromboembolic events in the pathogenesis of traumatic coagulopathy and correlation treatment has important significance in the process, to expand the number of samples, to carry out further research.

【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R651.15

【共引文献】