乳腺癌患者手术前后凝血变化的临床研究

发布时间：2018-05-03 16:02

本文选题：乳腺癌 + 凝血　；参考：《山东大学》2015年硕士论文

【摘要】：背景：通过不断的研究,人们逐渐认识到肿瘤和凝血系统之间的相互关系在乳腺癌进展的过程中的作用。事实上,凝血系统的各个部分,包括血小板、凝血酶原系统、和纤溶系统,均影响了许多已知的乳腺癌进展过程。术前,乳腺癌患者的凝血系统已经发生了变化。在患者中,原癌基因的激活和局部微环境的缺氧能促进组织因子的过度表达,激活凝血系统,引发体内凝血因子改变,导致血栓。因此,较良性患者,乳腺癌患者术前有可能出现凝血方面的改变,同时手术创伤也可以造成人体凝血系统发生改变,引发血栓的形成。乳腺癌患者术后引起凝血系统如何改变,目前尚不明确。乳腺癌患者术后可出现下肢静脉栓塞、肺栓塞等并发症。一旦这些并发症发生,都会对患者的身心和经济造成一定的压力,延长患者住院时间,造成不必要的经济花销,严重者甚至威胁到患者的生命。本文旨在探索乳腺癌患者术后凝血系统的改变。目的：1.探索乳腺癌患者手术前后凝血变化。2.乳腺癌患者手术前后凝血改变与临床病理学之间的关系。材料与方法病人数据：在2014.6.1—2014.12.31于山东大学齐鲁医院乳腺外科住院就诊的108名乳腺癌患者及20名良性乳腺肿瘤患者参与了研究。所有参与者均单纯行手术治疗,其中乳腺癌患者中,93名患者行单侧乳腺癌改良根治术,11名患者行单侧乳腺癌根治术,3名患者行双侧乳腺癌改良根治术。1例因病理类型较好,行单侧乳房皮下腺体切除术。病人的临床及病理特征见表1。方法：所有参与研究的患者均无肝肾疾病、血液病史,近2周内无血栓及感染性疾病史。所有患者均无使用阿司匹林、华法林等影响凝血或止血药物。所有患者在术前及术后第2天空腹状态下静脉采血。血液分析使用血细胞分析仪,所用试剂、质控物等均为原装配套试剂。采血使用的试管为EDTA抗凝管(采血量为5ml,内含3.6mg EDTA-K2)。试剂为原装配套试剂。PT、APTT使用凝同法测定。我们对患者的血浆凝血酶原时间(PT)、凝血酶原标准化比率(INR)、凝血酶原时间活动度(PTA)、凝血酶原时间比率(PTR)、活化部分凝血活酶时间(APTT)纤维蛋白原(Fib)、凝血酶时间(TT)、D-二聚体(D-dimer)进行统计和分析。所有乳腺癌患者均有病理学诊断。病理切片为石蜡切片,并经过HE染色。肿瘤分级是根据修改后的布鲁姆理查森评分系统。雌激素受体(ER)、孕激素受体(PR),和her-2状态评估的是通过使用适当的抗体进行检测。结果：1.从2014.6-2014.12,一共有108名患者参与了研究,平均年龄是50岁(年龄在27-76之间)(图1),在这108名患者中,均单纯经过手术治疗,手术方式包括单侧乳腺癌改良根治术(93例)、单侧乳腺癌根治术(11例)、双侧乳腺癌改良根治术(3例)、单纯乳腺切除术(1例)、三种。2.乳腺癌患者与良性乳腺肿瘤患者术前凝血的比较所有的良性乳腺肿瘤患者均无恶性肿瘤病史,通过比较两者术前的凝血系列指标,我们发现两者在APTT(P0.04)存在明显差异,而其他指标没有明显差异。3.乳腺癌患者与良性乳腺肿瘤患者术后凝血的比较我们可以看出FIB(P0.001)、APTT (P0.001)、TT(P0.003)、PTA (P0.05)存在明显差异,同时我们发现有些趋势,乳腺癌患者术后PT(P=0.09)、INR(P=0.06)、PTR(P=0.07)增高,但是都没有统计学意义。4.乳腺癌患者、良性乳腺肿瘤患者术前术后凝血变化的比较在乳腺癌患者中,术前术后所有的凝血系列指标的变化均有统计学意义。而在对照组中,只有(P=0.003)、FIB (P0.001)、TT (P=0.023)具有统计学意义.5.年龄(≥50),其术后凝血酶原活动度下降更明显(-11.5 vs-5.7,P=0.01),而且术后D-二聚体升高更明显(0.35 vs 0.14)。同时,年龄也影响了INR,年龄(≥50岁)的患者,其INR升高更明显(0.06 vs 0.04,P=0.04)。绝经期在一定程度上与年龄相关,两者存在共同点,都能使PTA下降(-11.7 vs-5.5,P=0.01)、INR升高(0.07 vs 0.03,P=0.01)更明显。两者也在一些项目上存在差异。绝经能使PT延长更明显(0.76 vs 0.36,P=0.01)、APTT下降不明显(-1.5 vs-2.6,P=0.01)同时绝经表现出一种趋势,术后D-二聚体升高更明显,但是P值大于0.05,因而也没有统计学意义。第一胎生育年龄(≥25岁)与第一胎生育年龄(25岁),两组在术后D-二聚体上存在差异。第一胎生育年龄(25岁)的患者其术后D-二聚体的水平升高(0.36 vs 0.15,P=0.05)更明显。而初潮年龄、家族恶性肿瘤病史、超重对乳腺癌患者术前术后凝血变化无影响。肿瘤的大小对手术前后凝血指标的变化没有影响,而淋巴结的状态,与一些指标相关。如淋巴结转移的患者,其手术前后PTA下降(-10.9 vs-5.8,P=0.02)、TT下降(-1.8 vs-1.3,P=0.04)的更明显。组织学越高,其术后PTA下降(-14.9 vs-7.5,P=0.02)的越明显,D-二聚体升高(0.52 vs 0.2)的越明显。雌激素受体的状态对乳腺癌患者手术前后凝血指标的变化没有影响,而孕激素受体阴性患者其术后纤维蛋白原升高(1.48vs 1.15,P=0.02)更明显。P53基因和Her-2基因对乳腺癌患者手术前后凝血指标改变没有影响。而Ki67(≥20%)的患者其术后纤维蛋白原升高(1.06 vs 1.46,P=0.04)更明显结论：像肿瘤的微环境和免疫反应一样,凝血系统被认为是一种影响肿瘤发展的的重要因素.相对于正常人或者良性肿瘤患者,乳腺癌患者体内凝血系统已经出现改变或者处于一种脆弱状态.通过实验组与对照组比较,我们看到APTT确实存在差异,而APTT是内源凝血系统较敏感和最为常用的筛选试验.乳腺癌患者与良性乳腺肿瘤患者手术前后凝血指标均发生了不同程度的改变,并且乳腺癌患者术后凝血指标与良性乳腺肿瘤患者之间存在差异。这说明乳腺癌患者术后其凝血系统改变更多、更大。相比于良性乳腺肿瘤患者,乳腺癌患者术后可能存在更高的血栓风险。此外年龄(≥50岁)、绝经、第一胎生育年龄(25岁)与乳腺癌患者手术前后凝血指标变化相关,而初潮年龄(15岁)、超重、家族恶性肿瘤病史对乳腺癌患者手术前后凝血改变无关。在病理特征上,肿瘤的大小对手术前后凝血指标的变化没有影响,而淋巴结的阳性则显示了一些阳性结果。组织学分级越高,其术后凝血指标改变越大,特别是引起D-二聚体水平升高的更明显,这说明高组织学分级的患者,其术后血栓风险增高。在免疫组化方面,雌激素与乳腺癌患者手术前后凝血指标变化无影响。而孕激素受体阴性的患者其纤维蛋白原水平升高,可能孕激素受体阳性是术后血栓的保护因素。P53基因和Her-2基因对乳腺癌患者手术前后凝血指标的变化没有影响,而Ki67≥20%的患者其术后纤维蛋白原水平升高的更明显,说明Ki67≥20%的乳腺癌患者其术后血栓风险增加。总之,乳腺癌患者手术前后,所有的凝血项目都发生了有意义的改变,而且这种改变是与绝经状态、淋巴结状态、组织学分级相关的。
[Abstract]:Background: through continuous research, people gradually recognize the role of the relationship between the tumor and the coagulation system in the progression of breast cancer. In fact, all parts of the blood clotting system, including platelets, prothrombin systems, and fibrinolytic systems, have affected the progress of many known breast cancer processes. The coagulation system has changed. In patients, the activation of the proto oncogene and the hypoxia in the local microenvironment can promote the overexpression of the tissue factor, activate the coagulation system, cause coagulation factor changes in the body and cause thrombus. Therefore, the patients with benign breast cancer may have the changes of coagulation before operation, and the surgical trauma is also possible. It can cause changes in the blood clotting system and the formation of thrombus. It is not clear how the blood clotting system changes after the operation of the breast cancer patients. The patients with breast cancer may have complications such as venous embolism and pulmonary embolism after operation. Once these complications occur, the patients' body and mind and economy can be caused by certain pressure and prolonged suffering. The purpose of this article is to explore the relationship between coagulation changes before and after operation of.2. breast cancer patients with.2. breast cancer and the relationship between coagulation changes and Clinicopathology before and after operation. Human data: 108 breast cancer patients and 20 benign breast cancer patients hospitalized at 2014.6.1 - 2014.12.31, Qilu Hospital, Shandong University, participated in the study. All the participants were treated with surgery alone. Among the patients with breast cancer, 93 patients underwent unilateral breast cancer modified radical mastectomy and 11 patients underwent unilateral breast cancer. Radical mastectomy, 3 patients underwent modified radical mastectomy for bilateral breast cancer,.1 cases with better pathological type, and unilateral breast subcutaneous gland resection. The clinical and pathological features of the patients were shown in table 1.. All the patients who participated in the study had no liver and kidney disease, blood history, no history of thrombus and infectious diseases within 2 weeks. All patients did not use aspirin. Lin, Hua Falin and other drugs affecting coagulation or hemostasis. All patients were collected in the venous blood under second sky abdominal conditions before and after operation. Blood analysis used blood cell analyzer, reagents used, quality control materials and so on. The test tube used for blood collection was EDTA anticoagulant tube (the amount of blood collection was 5ml, containing 3.6mg EDTA-K2). The reagent was the original kit. PT and APTT were measured by coagulant method. The plasma prothrombin time (PT), prothrombin standardization ratio (INR), prothrombin time activity (PTA), prothrombin time ratio (PTR), activated partial thromboplastin time (APTT) fibrinogen (Fib), thromboplastin time (TT), D- two polymer (D-dimer) were counted and analyzed. The patients with breast cancer have a pathological diagnosis. The pathological sections are paraffin sections and stained with HE. The tumor classification is based on the modified Blum Richardson scoring system. The estrogen receptor (ER), progesterone receptor (PR), and the HER-2 state are assessed by the use of appropriate antibodies. Results: 1. from 2014.6-2014.12, a total of 108. The patients were involved in the study, with an average age of 50 years (age 27-76) (Figure 1). In these 108 patients, all the patients were treated simply by surgical treatment, including unilateral breast cancer modified radical mastectomy (93 cases), unilateral radical mastectomy (11 cases), bilateral breast cancer modified radical mastectomy (3 cases), simple mammary gland resection (1 cases), three.2. breast cancer patients. Compared with preoperative coagulation, all patients with benign breast tumors had no history of malignant tumor. By comparing the preoperative coagulation series, we found that there were significant differences in APTT (P0.04), while other indicators did not significantly differ from.3. breast cancer patients and benign breast cancer patients. We can see that FIB (P0.001), APTT (P0.001), TT (P0.003), and PTA (P0.05) have obvious differences. At the same time, we found some trends in breast cancer patients, PT (P=0.09), INR (P=0.06), and increased, but no statistically significant breast cancer patients, patients with benign breast tumors were compared to breast cancer before and after operation. In the patients, all the changes of blood coagulation series before and after the operation were statistically significant, but in the control group, only (P=0.003), FIB (P0.001), TT (P=0.023) had statistical significance.5. age (> 50), and the decrease of prothrombin activity after operation was more obvious (-11.5 vs-5.7, P=0.01), and the increase of D- two polymer after operation was more obvious (0.35 vs 0.14). At the same time, age also affects INR, the age (50 years old) of the patients, the INR increase is more obvious (0.06 vs 0.04, P=0.04). Menopause is related to age to a certain extent, the two exist in common, can make PTA (-11.7 vs-5.5, P=0.01), INR increase (0.07 vs 0.03, P=0.01) more obvious. Both are also different in some items. Menopause can make PT The prolongation was more obvious (0.76 vs 0.36, P=0.01), and the decrease of APTT was not obvious (-1.5 vs-2.6, P=0.01) and menopause showed a trend, and the elevation of D- two polymer was more obvious after operation, but the value of P was greater than 0.05, so there was no statistical significance. The first birth age (25 years old) and the first birth age (25 years) and the two groups were different in the postoperative D- two polymer. The level of D- two polymer (0.36 vs 0.15, P=0.05) was more obvious after the first birth age (25 years old). The age of the menarche and the history of the family malignant tumor had no effect on the changes of blood coagulation before and after the operation. In patients with lymph node metastasis, PTA decreased (-10.9 vs-5.8, P=0.02) before and after operation, and TT decreased (-1.8 vs-1.3, P=0.04). The higher histology, the more obvious the postoperative PTA decreased (-14.9 vs-7.5, P=0.02), the more obvious the two polymer was raised (0.52) 0.2. The status of estrogen receptor in breast cancer patients' blood coagulation before and after operation The changes in the index were not affected, but the increase of fibrinogen (1.48vs 1.15, P=0.02) in the progesterone negative patients (P=0.02) was more obvious that the.P53 and Her-2 genes had no effect on the changes of blood coagulation indexes before and after the operation of breast cancer patients. And the postoperative increase of fibrinogen (1.06 vs 1.46, P=0.04) in patients with Ki67 (> 1.06) was more obvious: As the microenvironment of the tumor is the same as the immune response, the coagulation system is considered to be an important factor affecting the development of the tumor. Compared to the normal or benign tumor patients, the blood coagulation system in the breast cancer patients has changed or is in a fragile state. Compared with the control group, we see that the APTT does not exist. APTT is a more sensitive and most commonly used screening test for the internal blood coagulation system. The blood coagulation indexes of breast cancer patients and benign breast cancer patients vary in varying degrees, and there are differences between postoperative coagulation indexes and benign breast tumors in breast cancer patients. This shows the blood coagulation system of breast cancer patients after operation. Compared with benign breast cancer patients, breast cancer patients may have higher risk of thrombosis. Besides, age (50 years old), menopause, first birth age (25 years) are related to changes in blood coagulation indexes before and after operation of breast cancer patients, and the age of early menarche (15 years old), overweight, and family history of malignant tumor to breast cancer patients The changes in blood coagulation before and after the operation were not related. On pathological features, the size of the tumor did not affect the changes of blood coagulation indexes before and after the operation, while the positive lymph nodes showed some positive results. The higher the histological grade, the greater the changes in the postoperative coagulation index, especially the higher level of the D- two polymer, indicating the high organization score. There is no effect on the changes of blood coagulation indexes in the patients with breast cancer before and after operation, while the level of fibrinogen in the patients with progestin receptor negative is higher, and the positive of progestin receptor is the protective factor.P53 gene and the Her-2 gene for the operation of breast cancer patients. There was no effect on the changes in the index of the Precoagulation and blood coagulation, and the increased levels of fibrinogen in the patients with Ki67 > 20% were more obvious, indicating that the risk of postoperative thrombosis increased in the patients with Ki67 more than 20% of breast cancer. Lymph node status, histological grade related.

【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R737.9

【引证文献】