本文選題：凝血　切入點(diǎn)：因子　出處：《復(fù)旦大學(xué)》2013年博士論文

【摘要】：[第一部分] 研究目的： 通過(guò)監(jiān)測(cè)急性期單純性中重度顱腦損傷患者血漿凝血VII因子(FVII)水平的變化,了解FVII活性的變化與凝血功能障礙以及顱腦損傷后進(jìn)展性出血的關(guān)系。 研究方法： 2010至2012年期間,對(duì)急診入院的單純型中重度顱腦創(chuàng)傷患者進(jìn)行篩選,符合入選標(biāo)準(zhǔn)的患者記錄一般情況,并進(jìn)行傷后24小時(shí)內(nèi)靜脈血標(biāo)本采集,使用ELISA試劑盒檢測(cè)血漿FVIIa活性變化,同時(shí)記錄包括凝血酶原時(shí)間(PT)、部分活化凝血酶原時(shí)間(aPTT),凝血酶時(shí)間,纖維蛋白原(FIB),D—二聚體,和國(guó)際標(biāo)準(zhǔn)化比率(INR)在內(nèi)的凝血功能指標(biāo)。顱腦創(chuàng)傷相關(guān)的凝血病定義為血小板減少(120000/mm3),或INR上升(1.2),或者PT延長(zhǎng)(40秒)。根據(jù)影像學(xué)指標(biāo)判斷顱內(nèi)出血病灶情況。通過(guò)Logistic回歸模型分析凝血功能異常以及進(jìn)展性出血與顱腦創(chuàng)傷的關(guān)系。 研究結(jié)果： 共81例患者納入研究,其中發(fā)生凝血功能障礙者44例(54.3%)FVII的活性在伴有以及不伴有凝血功能障礙的患者中分別為85.69±34.88%和99.57%±29.37%,兩者差別顯著(p=0.041)。單純性顱腦創(chuàng)傷患者FVII活性77.5%產(chǎn)生凝血功能障礙的風(fēng)險(xiǎn)顯著增加(OR=5.52,95%CI1.82～16.68,p=0.03)。在存在進(jìn)展性出血與無(wú)進(jìn)展性出血的患者中,FVII的活性分別為70.76±18.21%和105.76±32.27%,兩者差別顯著(p0.001)。漸進(jìn)Logistic回歸分析顯示FVII77.5%是出血病灶進(jìn)展的獨(dú)立危險(xiǎn)因素(0R=4.53,95%CI1.62～12.67,p=0.004)。所有患者的死亡率為7.4%(n=6)。死亡患者中FVII的活性為91.44±47.19%,略低于生存患者的92.01±32.04%,但差異無(wú)統(tǒng)計(jì)學(xué)意義。 研究結(jié)論： 在急性單純型中重度顱腦創(chuàng)傷患者中,FVII活性與凝血功能狀態(tài)密切相關(guān),首次發(fā)現(xiàn)FVII活性77.5%是發(fā)生凝血功能障礙和發(fā)生進(jìn)展性出血的獨(dú)立危險(xiǎn)因素。[第二部分] 研究目的： 比較發(fā)生凝血功能障礙與凝血功能正常組患者在6個(gè)FVII多態(tài)性位點(diǎn)的差異,了解FVII基因多態(tài)性與凝血功能障礙的關(guān)系。 研究方法： 采取前瞻性、病例-對(duì)照研究,篩選2011年3月至2012年12月期間的急性單純型中重度顱腦創(chuàng)傷患者。采集入選患者的一般情況、診療信息以及預(yù)后信息。急性期采集患者外周靜脈血,用血液基因組DNA提取試劑盒提取外周血DNA,取2ul電泳(2%瓊脂糖凝膠,120V,20分鐘)檢測(cè)提取DNA的量,紫外分光光度儀檢測(cè)DNA濃度以及純度。采取限制性片段長(zhǎng)度多態(tài)性—聚合酶鏈反應(yīng)(PCR-RFLP)技術(shù)檢測(cè)方法檢測(cè)FVII基因-323P0/P10、R353Q、-401G/T、-402G/A、-670A/C和IVS7位點(diǎn)的基因表型。探討基因多態(tài)性與單純型顱腦創(chuàng)傷后凝血功能狀態(tài)之間的關(guān)系。 研究結(jié)果： 共入選91例患者,平均年齡51.67±16.67歲。其中發(fā)生凝血功能障礙者20例,凝血功能正常者77例。FVII基因-323P0/P10多態(tài)性PCR擴(kuò)增產(chǎn)物長(zhǎng)度為214bp和224bp, R353Q多態(tài)性PCR擴(kuò)增產(chǎn)物長(zhǎng)度為239bp,-401G/T和-402G/A多態(tài)性PCR擴(kuò)增產(chǎn)物長(zhǎng)度均為467bp,-670A/C多態(tài)性PCR擴(kuò)增產(chǎn)物長(zhǎng)度為192bp,IVS7多態(tài)性PCR擴(kuò)增產(chǎn)物長(zhǎng)度為443bp和480bp。Hardy-Weinberg遺傳平衡檢驗(yàn)顯示,各多態(tài)性位點(diǎn)的基因表型分布均符合Hardy-Weinberg平衡,來(lái)自同一群體。比較兩組患者的多態(tài)性分布情況顯示,-402G/A的基因多態(tài)性與凝血功能障礙的發(fā)病增加有關(guān)。隨訪分析顯示-402G/A和-670A/C基因型與患者出院時(shí)的GCS較低相關(guān)。 研究結(jié)論： FVII基因多態(tài)性的分析顯示,國(guó)人-402G/A與FVII血漿濃度水平較低以及凝血功能障礙的發(fā)生率升高相關(guān)。 [第三部分] 研究目的： 通過(guò)臨床前瞻性隊(duì)列研究,初步探索小劑量重組活化凝血VII因子(rFVIIa20mcg/kg)對(duì)顱腦外傷相關(guān)性凝血功能障礙的干預(yù)以及治療的作用。 研究方法： 篩選急診入院的伴凝血功能障礙的單純型顱腦創(chuàng)傷患者,將符合入選標(biāo)準(zhǔn)的患者按照糾正凝血功能異常的療法分為2組,一組在急性期接受早期小劑量rFVIIa(20mcg/kg)治療,另一組接受常規(guī)血制品治療糾正凝血功能異常。通過(guò)72小時(shí)的觀察,并對(duì)患者進(jìn)行隨訪,比較兩組治療期間凝血功能指標(biāo)的恢復(fù)情況、不良反應(yīng)、住院成本和預(yù)后的差異。 研究結(jié)果： 共納入86例患者,其中rFVIIa治療組27例,常規(guī)治療組59例。統(tǒng)計(jì)分析顯示,rFVIIa治療組與常規(guī)治療組的INR糾正程度分別為0.29±0.23和0.11±0.39,兩者差異顯著(p=0.01)。兩組72小時(shí)內(nèi)出現(xiàn)腦梗死病灶幾率分別為7.2%(2例)和8.5%(5例),兩者無(wú)顯著差異；兩組均未報(bào)道深靜脈血栓(DVT)的發(fā)生。隨訪30天死亡率在治療組和對(duì)照組分別為22.2%(6例)和32.2%(19例)。兩者無(wú)顯著差異。 研究結(jié)論： 小劑量rFVIIa在急性期可以有效糾正單純性中重度顱腦創(chuàng)傷患者的凝血功能異常,而不增加深靜脈血栓以及急性肺栓塞等血栓栓塞事件的發(fā)生。FVII在顱腦創(chuàng)傷相關(guān)性凝血功能障礙的發(fā)病以及治療過(guò)程中具有重要意義,值得擴(kuò)大樣本例數(shù),開(kāi)展進(jìn)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.

【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2013
【分類號(hào)】：R651.15

【共引文獻(xiàn)】

相關(guān)博士學(xué)位論文 前1條

1 田野;神經(jīng)細(xì)胞來(lái)源Microparticles在顱腦創(chuàng)傷相關(guān)凝血功能障礙發(fā)生中的機(jī)制研究[D];天津醫(yī)科大學(xué);2014年

相關(guān)碩士學(xué)位論文 前2條

1 穆福娜依·艾爾肯;靜脈血栓栓塞癥與凝血因子Ⅶ水平及其基因多態(tài)性的關(guān)聯(lián)研究[D];新疆醫(yī)科大學(xué);2013年

2 裴兵兵;凝血因子VII基因多態(tài)性與單純性顱腦創(chuàng)傷性凝血功能障礙的相關(guān)性研究[D];新鄉(xiāng)醫(yī)學(xué)院;2013年

，

本文編號(hào)：1680052