LRRFIP1基因干扰预防骨科深静脉血栓形成的实验研究
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摘要
研究背景：
深静脉血栓形成是骨科临床常见并发症之一，好发于下肢骨折患者，如血栓脱落可引起致命性肺栓塞，晚期常遗留静脉炎综合征，严重影响患者的康复及生命安全。新近有研究表明富亮氨酸重复序列相互作用蛋白1(LRRFIP1)可能与血栓的形成有重要联系。LRRFIP1基因及其编码的蛋白质，通过与血小板细胞膜上表达的相关蛋白相互作用，血小板细胞骨架的结构进而发生改变，影响血小板的凝血功能并导致血栓的形成。因此我们拟通过RNA干扰技术靶向沉默LRRFIP1基因，并建立动物模型，观察LRRFIP1基因对深静脉血栓形成的影响，探讨LRRFIP1基因沉默对预防骨科深静脉血栓形成的效果，为最终应用于在体基因治疗深静脉血栓提供相关实验依据。
研究方法：
1、LRRFIP1基因RNAi慢病毒载体的构建
设计并合成LRRFIP1基因靶向的双链DNA：根据GenBank报道的小鼠LRRFIP1基因序列，通过将Ambion公司的设计软件与RNA干扰序列的设计原则相结合，设计出3对针对LRRFIP1基因shRNA的寡核苷酸序列，分别构建质粒，转染293T细胞，RT-PCR和western blot测定沉默效率，使用沉默效率最高的质粒构建LRRFIP1基因RNAi的慢病毒载体。
2、小鼠骨髓细胞原代分离与培养
将1周龄的新生小鼠消毒后处死，分离骨髓细胞，接种于无菌培养瓶，置37℃、5%CO2恒温培养箱中培养。选取生长良好的第三代细胞进行后续实验。
3、小鼠骨髓细胞慢病毒感染
在24孔培养板接种若干孔，将3~5X104个目的细胞接种至每个孔内，50%左右细胞的贴壁率应在铺板时达到，每孔培养基体积为100μl；70%左右的细胞贴壁率应在进行病毒感染时达到。感染96小时后，在荧光倒置显微镜下观察荧光，估计慢病毒感染目的细胞的效率。
4、动物分组与给药
将健康成年雄性ICR小鼠(20±2g)随机分为：1)正常对照组(control)；2)假手术组(sham)：不给药；3)低分子肝素(LMWH)治疗组(LMWH)：术前通过尾静脉注射LMWH一次(2000U·kg~(-1))，术后每日注射一次LMWH (2000U·kg~(-1)·d~(-1))；4)模型组(model)：术前、术后每日注射等体积生理盐水；5) LRRFIP1shRNA治疗组(shRNA)：术前注射LRRFIP1shRNA慢病毒感染的小鼠BMCs (1×10~7cells/mouse)；6)阴性shRNA治疗组(Negative shRNA)：术前注射LRRFIP1阴性对照shRNA慢病毒感染的小鼠BMCs (1×10~7cells/mouse)；采用下腔静脉结扎法制作小鼠深静脉模型。
分别于术后第1、3、7天每组处死6只小鼠。称量血栓重量；酶联免疫吸附法(ELISA)检测小鼠血清p选择素及D二聚体水平，Western blot检测血栓中LRRFIP1蛋白的表达。
5、统计分析
计量资料表示为means±S.D。采用SPSS17.0for Windows进行统计分析，多组间比较采用单因素方差分析，多组间两两比较采用Fisher LSD分析。以p<0.05作为有统计学差异。
结果：
1.成功构建了携LRRFIP1shRNA的慢病毒载体，LRRFIP1shRNA转染后LRRFIP1基因及蛋白表达均显著降低；
2. LRRFIP1shRNA显著抑制血栓中LRRFIP1蛋白表达。在模型组中，在术后第1、3、7天血栓中LRRFIP1蛋白的表达显著降低(P<0.01)。在所观察的3个时间点上，使用LRRFIP1shRNA处理可以进一步抑制LRRFIP1在血栓中的表达，提示LRRFIP1shRNA慢病毒在体内可以有效抑制LRRFIP1的表达。但低分子肝素和阴性shRNA对LRRFIP1表达无影响。
3. LRRFIP1shRNA显著抑制小鼠下肢静脉血栓形成。LRRFIP1shRNA抑制体内血栓形成明显的。在术后第7天，模型组小鼠血栓重量为8.63±0.40mg，在LRRFIP1shRNA治疗组，血栓重量降低到2.15±0.57mg (P<0.01)。血栓形成抑制率为75.10%。而在低分子肝素治疗组和阴性shRNA治疗组，血栓重量分别为2.20±0.33mg和6.47±0.66mg，血栓形成抑制率分别为74.50%and25.02%。
4. LRRFIP1shRNA能够降低小鼠血清p-选择素和d-二聚体水平。与正常对照组和假手术组相比，模型组血浆P-选择素水平明显增加(P<0.01)。LRRFIP1shRNA治疗显着降低血浆P-选择素水平(P<0.01)。血浆D-二聚体水平在模型组也明显升高(P<0.01)，而LRRFIP1shRNA治疗可显著地抑制D-二聚体水平的上调(P<0.01)。然而，低分子肝素和阴性shRNA对血浆P-选择素、D-二聚体水平的影响不大。
结论：
1.成功构建了LRRFIP1shRNA表达质粒及慢病毒载体；
2. LRRFIP1shRNA在体内、外均能够抑制LRRFIP1mRNA和蛋白表达；
3. LRRFIP1基因干扰能抑制小鼠下肢深静脉血栓形成；
4. LRRFIP1shRNA抑制深静脉血栓形成与其降低血浆p-选择素和d-二聚体水平有关。
Background
Deep venous thrombosis (DVT) is one of the common complications in the departmentof orthopedics, occuring in the patients with fracture of lower limb. If the thrombi fall off, itcan cause fatal pulmonary embolism, and often left phlebitis syndrome, which seriouslyaffect the rehabilitation and life safety of patients. Recent studies have shown that leucinerich repeat interacting protein1(LRRFIP1) may have important links with thrombosis.LRRFIP1gene and its encoded protein, may interact with the protein on platelet membrane,then change the platelet cytoskeleton structure, and affect the coagulation function inplatelet and thrombus formation. So we proposed to observe the effect of LRRFIP1gene onthe formation of DVT through silencing LRRFIP1by RNA interference, investigate theeffect of LRRFIP1gene silencing on the prevention of DVT and provide the experimentalbasis for the final application of gene therapy in the treatment of DVT in vivo.
Methods
1. Construction of lentiviral vector carrying LRRFIP1shRNA
Design and synthesize LRRFIP1gene targeted double-strand DNA: according to therat LRRFIP1gene sequence reported by GenBank, using the design software of Ambioncompany, according to RNA interference sequence design principles, design3againstLRRFIP1gene shRNA oligonucleotide sequence. Construct and transfect the plasmids into293T cells, RT-PCR and Western blot methods determine the silencing efficiency. Themost efficient shRNA plasmid was used to package the lentiviral vectors.
2. Isolation and culture of the primary mouse bone marrow cells (BMCs)
One-week old rats were sacrificed after disinfection. BMCs were isolated andincubated in37C,5%CO2incubator. P3cells were selected for the followingexperiments.
3. Infection of BMCs with lentivirus
BMCs were seeded in24-well plates at a density of3~5X104/well. When theconfluence reached70%, the BMCs were infected with the lentivirus. After96h, thefluorescence was observed under the fluorescent microscope, and the infection efficiency ofthe lentivirus was estimated.
4. Animal grouping and treatment
Healthy adult male ICR mice (20±2g) were randomly divided into the followinggroups:1) normal control group (control);2) the sham operation group (sham);3) lowmolecular weight heparin (LMWH) treatment group (LMWH): mice were injected withLMWH (2000U kg~(-1)) once by tail vein preoperatively, and postoperatively injected withLMWH (2000U kg~(-1) d~(-1)) daily;4) model group (model): mice were injected with normalsaline daily;5) LRRFIP1shRNA treatment group (shRNA): mice were injected with BMCsinfected with LRRFIP1shRNA lentivirus before operation (1×10~7cells/mouse);6)negative shRNA treatment group (Negative shRNA): mice were injected with BMCsinfected with negative LRRFIP1shRNA lentivirus before operation (1×10~7cells/mouse).
DVT mouse model was produced by ligation of inferior vena cava. Six mice in eachgroup were sacrificed on the1st, the3rdand the7thday post operation. The weight ofthrombus was determined; enzyme linked immunosorbent assay (ELISA) detection wasused to examine serum P-selectin and d-dimer levels; expression of LRRFIP1protein inthrombosis was determined by Western blot.
5. Statistical analysis
Measurement data were expressed as means±S.D. SPSS17for Windows was usedfor statistical analysis. Statistical analysis was programmed by one-way analysis ofvariance (ANOVA). Difference was regarded as significant when P <0.05.
Results
1. The lentiviral vector carrying LRRFIP1shRNA was successfully constructed.transfection of LRRFIP1shRNA significantly decreased LRRFIP1mRNA and proteinexpression;
2. LRRFIP1shRNA significantly inhibited the expression of LRRFIP1protein inthrombus. In the model group, the expression of LRRFIP1in thrombus decreasedsignificantly (P<0.01) on the1st,3rdand7th days after operation. At the3time points observed, LRRFIP1shRNA treatment further suppressed LRRFIP1expression in thrombus,indicating LRRFIP1shRNA lentivirus can effectively inhibit the LRRFIP1expression. Butthe LMWH and negative shRNA had no effect on the expression of LRRFIP1.
3. LRRFIP1shRNA significantly inhibited mice DVT formations. LRRFIP1shRNAinhibited thrombus formation in vivo apparently. On the7th day post operation, the weightof thrombus in model group was8.63±0.40mg, whereas the thrombus weight reduced to2.15±0.57mg (P<0.01) in the LRRFIP1shRNA treatment group, with a thrombosisinhibition rate of75.10%. In the LMWH treatment group and shRNA negative group, thethrombus weight were2.20±0.33mg and6.47±0.66mg, with thrombosis inhibition ratesof74.50%and25.02%respectively.
4. LRRFIP1shRNA can reduce the serum levels of p-selectin and d-dimer. Comparedwith the normal control group and sham operation group, the plasma level of P-selectinsignificantly increased (P<0.01) in model group,. LRRFIP1shRNA treatment significantlydecreased the plasma level of P-selectin (P<0.01). The plasma level of d-dimer in modelgroup was also significantly increased (P<0.01), and LRRFIP1shRNA treatmentsignificantly inhibited the up-regulation of d-dimer levels (P<0.01). However, LMWH andnegative shRNA showed little effect on plasma P-selectin and d-dimer levels.
Conclusion
1. The LRRFIP1shRNA expression plasmid and lentiviral vector were successfullyconstructed;
2. LRRFIP1shRNA is able to inhibit LRRFIP1mRNA and protein expression in vitroand in vivo;
3. LRRFIP1gene knockout inhibits deep venous thrombosis formation in mice;
4. Inhibition of deep vein thrombosis with LRRFIP1shRNA is associated with thedecrease of plasma p-selectin and d-dimer levels.
深静脉血栓形成是骨科临床常见并发症之一，好发于下肢骨折患者，如血栓脱落可引起致命性肺栓塞，晚期常遗留静脉炎综合征，严重影响患者的康复及生命安全。新近有研究表明富亮氨酸重复序列相互作用蛋白1(LRRFIP1)可能与血栓的形成有重要联系。LRRFIP1基因及其编码的蛋白质，通过与血小板细胞膜上表达的相关蛋白相互作用，血小板细胞骨架的结构进而发生改变，影响血小板的凝血功能并导致血栓的形成。因此我们拟通过RNA干扰技术靶向沉默LRRFIP1基因，并建立动物模型，观察LRRFIP1基因对深静脉血栓形成的影响，探讨LRRFIP1基因沉默对预防骨科深静脉血栓形成的效果，为最终应用于在体基因治疗深静脉血栓提供相关实验依据。
研究方法：
1、LRRFIP1基因RNAi慢病毒载体的构建
设计并合成LRRFIP1基因靶向的双链DNA：根据GenBank报道的小鼠LRRFIP1基因序列，通过将Ambion公司的设计软件与RNA干扰序列的设计原则相结合，设计出3对针对LRRFIP1基因shRNA的寡核苷酸序列，分别构建质粒，转染293T细胞，RT-PCR和western blot测定沉默效率，使用沉默效率最高的质粒构建LRRFIP1基因RNAi的慢病毒载体。
2、小鼠骨髓细胞原代分离与培养
将1周龄的新生小鼠消毒后处死，分离骨髓细胞，接种于无菌培养瓶，置37℃、5%CO2恒温培养箱中培养。选取生长良好的第三代细胞进行后续实验。
3、小鼠骨髓细胞慢病毒感染
在24孔培养板接种若干孔，将3~5X104个目的细胞接种至每个孔内，50%左右细胞的贴壁率应在铺板时达到，每孔培养基体积为100μl；70%左右的细胞贴壁率应在进行病毒感染时达到。感染96小时后，在荧光倒置显微镜下观察荧光，估计慢病毒感染目的细胞的效率。
4、动物分组与给药
将健康成年雄性ICR小鼠(20±2g)随机分为：1)正常对照组(control)；2)假手术组(sham)：不给药；3)低分子肝素(LMWH)治疗组(LMWH)：术前通过尾静脉注射LMWH一次(2000U·kg~(-1))，术后每日注射一次LMWH (2000U·kg~(-1)·d~(-1))；4)模型组(model)：术前、术后每日注射等体积生理盐水；5) LRRFIP1shRNA治疗组(shRNA)：术前注射LRRFIP1shRNA慢病毒感染的小鼠BMCs (1×10~7cells/mouse)；6)阴性shRNA治疗组(Negative shRNA)：术前注射LRRFIP1阴性对照shRNA慢病毒感染的小鼠BMCs (1×10~7cells/mouse)；采用下腔静脉结扎法制作小鼠深静脉模型。
分别于术后第1、3、7天每组处死6只小鼠。称量血栓重量；酶联免疫吸附法(ELISA)检测小鼠血清p选择素及D二聚体水平，Western blot检测血栓中LRRFIP1蛋白的表达。
5、统计分析
计量资料表示为means±S.D。采用SPSS17.0for Windows进行统计分析，多组间比较采用单因素方差分析，多组间两两比较采用Fisher LSD分析。以p<0.05作为有统计学差异。
结果：
1.成功构建了携LRRFIP1shRNA的慢病毒载体，LRRFIP1shRNA转染后LRRFIP1基因及蛋白表达均显著降低；
2. LRRFIP1shRNA显著抑制血栓中LRRFIP1蛋白表达。在模型组中，在术后第1、3、7天血栓中LRRFIP1蛋白的表达显著降低(P<0.01)。在所观察的3个时间点上，使用LRRFIP1shRNA处理可以进一步抑制LRRFIP1在血栓中的表达，提示LRRFIP1shRNA慢病毒在体内可以有效抑制LRRFIP1的表达。但低分子肝素和阴性shRNA对LRRFIP1表达无影响。
3. LRRFIP1shRNA显著抑制小鼠下肢静脉血栓形成。LRRFIP1shRNA抑制体内血栓形成明显的。在术后第7天，模型组小鼠血栓重量为8.63±0.40mg，在LRRFIP1shRNA治疗组，血栓重量降低到2.15±0.57mg (P<0.01)。血栓形成抑制率为75.10%。而在低分子肝素治疗组和阴性shRNA治疗组，血栓重量分别为2.20±0.33mg和6.47±0.66mg，血栓形成抑制率分别为74.50%and25.02%。
4. LRRFIP1shRNA能够降低小鼠血清p-选择素和d-二聚体水平。与正常对照组和假手术组相比，模型组血浆P-选择素水平明显增加(P<0.01)。LRRFIP1shRNA治疗显着降低血浆P-选择素水平(P<0.01)。血浆D-二聚体水平在模型组也明显升高(P<0.01)，而LRRFIP1shRNA治疗可显著地抑制D-二聚体水平的上调(P<0.01)。然而，低分子肝素和阴性shRNA对血浆P-选择素、D-二聚体水平的影响不大。
结论：
1.成功构建了LRRFIP1shRNA表达质粒及慢病毒载体；
2. LRRFIP1shRNA在体内、外均能够抑制LRRFIP1mRNA和蛋白表达；
3. LRRFIP1基因干扰能抑制小鼠下肢深静脉血栓形成；
4. LRRFIP1shRNA抑制深静脉血栓形成与其降低血浆p-选择素和d-二聚体水平有关。
Background
Deep venous thrombosis (DVT) is one of the common complications in the departmentof orthopedics, occuring in the patients with fracture of lower limb. If the thrombi fall off, itcan cause fatal pulmonary embolism, and often left phlebitis syndrome, which seriouslyaffect the rehabilitation and life safety of patients. Recent studies have shown that leucinerich repeat interacting protein1(LRRFIP1) may have important links with thrombosis.LRRFIP1gene and its encoded protein, may interact with the protein on platelet membrane,then change the platelet cytoskeleton structure, and affect the coagulation function inplatelet and thrombus formation. So we proposed to observe the effect of LRRFIP1gene onthe formation of DVT through silencing LRRFIP1by RNA interference, investigate theeffect of LRRFIP1gene silencing on the prevention of DVT and provide the experimentalbasis for the final application of gene therapy in the treatment of DVT in vivo.
Methods
1. Construction of lentiviral vector carrying LRRFIP1shRNA
Design and synthesize LRRFIP1gene targeted double-strand DNA: according to therat LRRFIP1gene sequence reported by GenBank, using the design software of Ambioncompany, according to RNA interference sequence design principles, design3againstLRRFIP1gene shRNA oligonucleotide sequence. Construct and transfect the plasmids into293T cells, RT-PCR and Western blot methods determine the silencing efficiency. Themost efficient shRNA plasmid was used to package the lentiviral vectors.
2. Isolation and culture of the primary mouse bone marrow cells (BMCs)
One-week old rats were sacrificed after disinfection. BMCs were isolated andincubated in37C,5%CO2incubator. P3cells were selected for the followingexperiments.
3. Infection of BMCs with lentivirus
BMCs were seeded in24-well plates at a density of3~5X104/well. When theconfluence reached70%, the BMCs were infected with the lentivirus. After96h, thefluorescence was observed under the fluorescent microscope, and the infection efficiency ofthe lentivirus was estimated.
4. Animal grouping and treatment
Healthy adult male ICR mice (20±2g) were randomly divided into the followinggroups:1) normal control group (control);2) the sham operation group (sham);3) lowmolecular weight heparin (LMWH) treatment group (LMWH): mice were injected withLMWH (2000U kg~(-1)) once by tail vein preoperatively, and postoperatively injected withLMWH (2000U kg~(-1) d~(-1)) daily;4) model group (model): mice were injected with normalsaline daily;5) LRRFIP1shRNA treatment group (shRNA): mice were injected with BMCsinfected with LRRFIP1shRNA lentivirus before operation (1×10~7cells/mouse);6)negative shRNA treatment group (Negative shRNA): mice were injected with BMCsinfected with negative LRRFIP1shRNA lentivirus before operation (1×10~7cells/mouse).
DVT mouse model was produced by ligation of inferior vena cava. Six mice in eachgroup were sacrificed on the1st, the3rdand the7thday post operation. The weight ofthrombus was determined; enzyme linked immunosorbent assay (ELISA) detection wasused to examine serum P-selectin and d-dimer levels; expression of LRRFIP1protein inthrombosis was determined by Western blot.
5. Statistical analysis
Measurement data were expressed as means±S.D. SPSS17for Windows was usedfor statistical analysis. Statistical analysis was programmed by one-way analysis ofvariance (ANOVA). Difference was regarded as significant when P <0.05.
Results
1. The lentiviral vector carrying LRRFIP1shRNA was successfully constructed.transfection of LRRFIP1shRNA significantly decreased LRRFIP1mRNA and proteinexpression;
2. LRRFIP1shRNA significantly inhibited the expression of LRRFIP1protein inthrombus. In the model group, the expression of LRRFIP1in thrombus decreasedsignificantly (P<0.01) on the1st,3rdand7th days after operation. At the3time points observed, LRRFIP1shRNA treatment further suppressed LRRFIP1expression in thrombus,indicating LRRFIP1shRNA lentivirus can effectively inhibit the LRRFIP1expression. Butthe LMWH and negative shRNA had no effect on the expression of LRRFIP1.
3. LRRFIP1shRNA significantly inhibited mice DVT formations. LRRFIP1shRNAinhibited thrombus formation in vivo apparently. On the7th day post operation, the weightof thrombus in model group was8.63±0.40mg, whereas the thrombus weight reduced to2.15±0.57mg (P<0.01) in the LRRFIP1shRNA treatment group, with a thrombosisinhibition rate of75.10%. In the LMWH treatment group and shRNA negative group, thethrombus weight were2.20±0.33mg and6.47±0.66mg, with thrombosis inhibition ratesof74.50%and25.02%respectively.
4. LRRFIP1shRNA can reduce the serum levels of p-selectin and d-dimer. Comparedwith the normal control group and sham operation group, the plasma level of P-selectinsignificantly increased (P<0.01) in model group,. LRRFIP1shRNA treatment significantlydecreased the plasma level of P-selectin (P<0.01). The plasma level of d-dimer in modelgroup was also significantly increased (P<0.01), and LRRFIP1shRNA treatmentsignificantly inhibited the up-regulation of d-dimer levels (P<0.01). However, LMWH andnegative shRNA showed little effect on plasma P-selectin and d-dimer levels.
Conclusion
1. The LRRFIP1shRNA expression plasmid and lentiviral vector were successfullyconstructed;
2. LRRFIP1shRNA is able to inhibit LRRFIP1mRNA and protein expression in vitroand in vivo;
3. LRRFIP1gene knockout inhibits deep venous thrombosis formation in mice;
4. Inhibition of deep vein thrombosis with LRRFIP1shRNA is associated with thedecrease of plasma p-selectin and d-dimer levels.
引文
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1Geisse S,Henke M. Large-scale transient transfection of mammalian cells: a newly emerging attractive option forrecombinant protein production [J].Struct Funct Genomics,2005,6(2-3):165-170.
2Sinn PL, Sauter SL,McCray PB. Gene therapy progress and prospects: development of improved lentiviral andretroviral vectors-design, biosafety and production [J]. Gene Ther,2005,12:1089-1098.
3Zuferey R,Nagy D,Mandel RJ, et al. Mutiply attenuated lentivi ralvector achieved eficient gene delivery in vivo [J].Nat Biotech-nol,1997,15(9):871-875.
4Miyoshi H,Smith KA, Mosier DE,et al. Transduction of human CD34+Cells that mediate long-term engraftment ofNOD/SCID mice by HIV Vectors [J]. Science,1999,283(5402):682-686.
5Naldini L,Blomer U,Gage FH, et al. Eficient h'ansfer, integration, and sustained long-term expression of the transgenein adult rat brains injected with a lentiviral vector [J]. Proc Natl Acad Sci,1996,92(21):11382-11388.
6Naldini L,Blomer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviralvector [J]. Science,1996,272(5259):263-267.
7Valpe TA,Kidner C,Hall IM, et al. Regulation of heterochromatic silencing and histone H3lysine-9methylation byRNAi [J]. Science,2002,297(5588):1833-1837.
8Reinhart BJ,Bartel DP. Small RNAs correspond to centromere heterochromatic repeats. Science,2002,297(5588):1831.Thromb Haemost，2001，86:1331-1333.
1Reyers I，Mussoni L，Donati MB，et al. Failure of aspirin at different doses to modify experimental thrombosis inrats[J]. Thromb Res，1980，18(5):669-674
2Chao Wang, Fang Yang, Zhihong Xu,et al. Intravenous release of NO from lipidic microbubbles accelerates deep veinthrombosis resolution in a rat model[J]. Thromb Res，2013，131(1):31-38.
3Seiji K, Toshio U, Minori S, et al. Antithrombotic and anticoagulant effects of direct factor Xa inhibitor darexaban inrat and rabbit models of venous thrombosis[J]. European Journal of Pharmacology，2013，699(1):40-47.
4张春强，黄河，赵学凌，等.两种创伤性深静脉血栓大鼠模型中炎症相关基因的表达研究[J].生物医学工程研究，2008，26(1):66-70.
1Amarzguioui M, Rossi JJ, Kim D. Approaches for chemically synthesized siRNA and vector-mediated RNAi. FEBSLett.2005;579:5974–5981.
2Li CX, Parker A, Menocal E, Xiang S, et al.Delivery of RNA interference. Cell Cycle.2006;5:2103–2109.
3Woods NB, Ooka A, Karlsson S. Development of gene therapy for hematopoietic stem cells using lentiviral vectors.Leukemia.2002;16:563–569.
4Rubinson DA, Dillon CP, Kwiatkowski AV,et al. A lentivirus-based system to functionally silence genes in primarymammalian cells, stem cells and transgenic mice by RNA interference.Nat Genet.2003;33:401–406.
5Thomas KR, Capecchi MR. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell.1987;51:503–512.
6Offermanns S. Activation of platelet function through G protein-coupled receptors. Circ Res.2006;99:1293–1304.
7Watson SP, Gibbins J. Collagen receptor signalling in platelets: extending the role of the ITAM. Immunol Today.1998;19:260–264.
8Pasquet JM, Gross B, Quek L,et al. LAT is required for tyrosine phosphorylation of phospholipase cgamma2andplatelet activation by the collagen receptor GPVI. Mol Cell Biol.1999;19:8326–8334.
9Clements JL, Lee JR, Gross B, et al. Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice. J Clin Invest.1999;103:19–25.
10Tsukasa O, Yuji K, Akira I,et al. Silencing of a Targeted Protein in In Vivo Platelets Using a Lentiviral VectorDelivering Short Hairpin RNA Sequence. Arterioscler Thromb Vasc Biol2007;27;2266-2272;
1Liew A, Douketis J. Initial and long-term treatment of deep venous thrombosis: Recent clinical trials and their impacton patient management. Expert Opin Pharmacother.2013
2林崇明,刘卓,王建雄,董辉详,黄长明.骨科大手术后深静脉血栓的防治现状及进展.临床军医杂志.2011;39:1245-1247
3邱贵兴.预防骨科大手术后深静脉血栓形成的专家建议.继续医学教育.2006;20:8-15
4Rathbun S. Cardiology patient pages. The surgeon general's call to action to prevent deep vein thrombosis andpulmonary embolism. Circulation.2009;119:e480-482
5Engelberger RP, Kucher N. Management of deep vein thrombosis of the upper extremity. Circulation.2012;126:768-773
6张惠明,张力,赵育强,周晓丽,莫海婷.益气活血法治疗大鼠深静脉血栓的实验研究.中医药信息.2009;26:115-117
7陈以宽,朱仕钦,罗文军,孙建明,沈庆明.手术与非手术治疗下肢深静脉血栓形成疗效对比分析.中国实用外科杂志.2008;28:139-141
1Bates SM, Ginsberg JS. Clinical practice. Treatment of deep-vein thrombosis. N Engl J Med.2004;351:268-277
2练琼芳.低分子肝素钙对预防下肢深静脉血栓形成的观察.医学信息：上旬刊.2011;24:3801-3802
3Alban S. Adverse effects of heparin. Handb Exp Pharmacol.2012:211-263
4Jensen CD, Steval A, Partington PF, Reed MR, Muller SD. Return to theatre following total hip and knee replacement,before and after the introduction of rivaroxaban: A retrospective cohort study. J Bone Joint Surg Br.2011;93:91-95
5Reed AL, Yamazaki H, Kaufman JD, Rubinstein Y, Murphy B, Johnson AC. Molecular cloning and characterization ofa transcription regulator with homology to gc-binding factor. J Biol Chem.1998;273:21594-21602
6Goodall AH, Burns P, Salles I, Macaulay IC, Jones CI, Ardissino D, de Bono B, Bray SL, Deckmyn H, Dudbridge F,Fitzgerald DJ, Garner SF, Gusnanto A, Koch K, Langford C, O'Connor MN, Rice CM, Stemple D, Stephens J, Trip MD,Zwaginga JJ, Samani NJ, Watkins NA, Maguire PB, Ouwehand WH. Transcription profiling in human platelets revealslrrfip1as a novel protein regulating platelet function. Blood.2010;116:4646-4656
7Steele BM, Harper MT, Macaulay IC, Morrell CN, Perez-Tamayo A, Foy M, Habas R, Poole AW, Fitzgerald DJ,Maguire PB. Canonical wnt signaling negatively regulates platelet function. Proc Natl Acad Sci U S A.2009;106:19836-19841
1Ley K. The role of selectins in inflammation and disease. Trends Mol Med.2003;9:263-268
2Frenette PS, Denis CV, Weiss L, Jurk K, Subbarao S, Kehrel B, Hartwig JH, Vestweber D, Wagner DD. P-selectinglycoprotein ligand1(psgl-1) is expressed on platelets and can mediate platelet-endothelial interactions in vivo. J ExpMed.2000;191:1413-1422
3Pabinger I, Ay C. Biomarkers and venous thromboembolism. Arterioscler Thromb Vasc Biol.2009;29:332-336
4Kawabata K, Nagake Y, Shikata K, Fukuda S, Nakazono H, Takahashi M, Ichikawa H, Makino H. Soluble p-selectin isreleased from activated platelets in vivo during hemodialysis. Nephron.1998;78:148-155
5Blann AD, Noteboom WM, Rosendaal FR. Increased soluble p-selectin levels following deep venous thrombosis:Cause or effect? Br J Haematol.2000;108:191-193
6Smith A, Quarmby JW, Collins M, Lockhart SM, Burnand KG. Changes in the levels of soluble adhesion molecules andcoagulation factors in patients with deep vein thrombosis. Thromb Haemost.1999;82:1593-1599
7Myers DD, Jr., Henke PK, Wrobleski SK, Hawley AE, Farris DM, Chapman AM, Knipp BS, Thanaporn P, Schaub RG,Greenfield LJ, Wakefield TW. P-selectin inhibition enhances thrombus resolution and decreases vein wall fibrosis in a ratmodel. J Vasc Surg.2002;36:928-938
8Sullivan VV, Hawley AE, Farris DM, Knipp BS, Varga AJ, Wrobleski SK, Thanapron P, Eagleton MJ, Myers DD,Fowlkes JB, Wakefield TW. Decrease in fibrin content of venous thrombi in selectin-deficient mice. J Surg Res.2003;109:1-7
1Eppihimer MJ, Schaub RG. P-selectin-dependent inhibition of thrombosis during venous stasis. Arterioscler Thromb
2Vasc Biol.2000;20:2483-2488Myers D, Wrobleski S, Londy F, Fex B, Hawley A, Schaub R, Greenfield L, Wakefield T. New and effective treatmentof experimentally induced venous thrombosis with anti-inflammatory rpsgl-ig. Thromb Haemost.2002;87:374-382
3Gremmel T, Ay C, Seidinger D, Pabinger I, Panzer S, Koppensteiner R. Soluble p-selectin, d-dimer, andhigh-sensitivity c-reactive protein after acute deep vein thrombosis of the lower limb. J Vasc Surg.2011;54:48S-55S
4Eichinger S, Minar E, Bialonczyk C, Hirschl M, Quehenberger P, Schneider B, Weltermann A, Wagner O, Kyrle PA.D-dimer levels and risk of recurrent venous thromboembolism. JAMA.2003;290:1071-1074
5Mauriello A, Sangiorgi G, Palmieri G, Virmani R, Holmes DR, Jr., Schwartz RS, Pistolese R, Ippoliti A, Spagnoli LG.Hyperfibrinogenemia is associated with specific histocytological composition and complications of atheroscleroticcarotid plaques in patients affected by transient ischemic attacks. Circulation.2000;101:744-750
6Bates SM. D-dimer assays in diagnosis and management of thrombotic and bleeding disorders. Semin Thromb Hemost.2012;38:673-682
7Kakkar VV, Lawrence D. Hemodynamic and clinical assessment after therapy for acute deep vein thrombosis. Aprospective study. Am J Surg.1985;150:54-63
8Myers DD, Jr., Henke PK, Wrobleski SK, Hawley AE, Farris DM, Chapman AM, Knipp BS, Thanaporn P, Schaub RG,Greenfield LJ, Wakefield TW. P-selectin inhibition enhances thrombus resolution and decreases vein wall fibrosis in a rat
9model. J Vasc Surg.2002;36:928-938Greenfield LJ, Proctor MC. Recurrent thromboembolism in patients with vena cava filters. J Vasc Surg.2001;33:510-514
1Myers DD, Jr., Henke PK, Bedard PW, Wrobleski SK, Kaila N, Shaw G, Meier TR, Hawley AE, Schaub RG, WakefieldTW. Treatment with an oral small molecule inhibitor of p selectin (psi-697) decreases vein wall injury in a rat stenosismodel of venous thrombosis. J Vasc Surg.2006;44:625-632
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2Chao Wang, Fang Yang, Zhihong Xu,et al. Intravenous release of NO from lipidic microbubbles accelerates deep veinthrombosis resolution in a rat model[J]. Thromb Res，2013，131(1):31-38.
3Seiji K, Toshio U, Minori S, et al. Antithrombotic and anticoagulant effects of direct factor Xa inhibitor darexaban inrat and rabbit models of venous thrombosis[J]. European Journal of Pharmacology，2013，699(1):40-47.
4张春强，黄河，赵学凌，等.两种创伤性深静脉血栓大鼠模型中炎症相关基因的表达研究[J].生物医学工程研究，2008，26(1):66-70.
1Amarzguioui M, Rossi JJ, Kim D. Approaches for chemically synthesized siRNA and vector-mediated RNAi. FEBSLett.2005;579:5974–5981.
2Li CX, Parker A, Menocal E, Xiang S, et al.Delivery of RNA interference. Cell Cycle.2006;5:2103–2109.
3Woods NB, Ooka A, Karlsson S. Development of gene therapy for hematopoietic stem cells using lentiviral vectors.Leukemia.2002;16:563–569.
4Rubinson DA, Dillon CP, Kwiatkowski AV,et al. A lentivirus-based system to functionally silence genes in primarymammalian cells, stem cells and transgenic mice by RNA interference.Nat Genet.2003;33:401–406.
5Thomas KR, Capecchi MR. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell.1987;51:503–512.
6Offermanns S. Activation of platelet function through G protein-coupled receptors. Circ Res.2006;99:1293–1304.
7Watson SP, Gibbins J. Collagen receptor signalling in platelets: extending the role of the ITAM. Immunol Today.1998;19:260–264.
8Pasquet JM, Gross B, Quek L,et al. LAT is required for tyrosine phosphorylation of phospholipase cgamma2andplatelet activation by the collagen receptor GPVI. Mol Cell Biol.1999;19:8326–8334.
9Clements JL, Lee JR, Gross B, et al. Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice. J Clin Invest.1999;103:19–25.
10Tsukasa O, Yuji K, Akira I,et al. Silencing of a Targeted Protein in In Vivo Platelets Using a Lentiviral VectorDelivering Short Hairpin RNA Sequence. Arterioscler Thromb Vasc Biol2007;27;2266-2272;
1Liew A, Douketis J. Initial and long-term treatment of deep venous thrombosis: Recent clinical trials and their impacton patient management. Expert Opin Pharmacother.2013
2林崇明,刘卓,王建雄,董辉详,黄长明.骨科大手术后深静脉血栓的防治现状及进展.临床军医杂志.2011;39:1245-1247
3邱贵兴.预防骨科大手术后深静脉血栓形成的专家建议.继续医学教育.2006;20:8-15
4Rathbun S. Cardiology patient pages. The surgeon general's call to action to prevent deep vein thrombosis andpulmonary embolism. Circulation.2009;119:e480-482
5Engelberger RP, Kucher N. Management of deep vein thrombosis of the upper extremity. Circulation.2012;126:768-773
6张惠明,张力,赵育强,周晓丽,莫海婷.益气活血法治疗大鼠深静脉血栓的实验研究.中医药信息.2009;26:115-117
7陈以宽,朱仕钦,罗文军,孙建明,沈庆明.手术与非手术治疗下肢深静脉血栓形成疗效对比分析.中国实用外科杂志.2008;28:139-141
1Bates SM, Ginsberg JS. Clinical practice. Treatment of deep-vein thrombosis. N Engl J Med.2004;351:268-277
2练琼芳.低分子肝素钙对预防下肢深静脉血栓形成的观察.医学信息：上旬刊.2011;24:3801-3802
3Alban S. Adverse effects of heparin. Handb Exp Pharmacol.2012:211-263
4Jensen CD, Steval A, Partington PF, Reed MR, Muller SD. Return to theatre following total hip and knee replacement,before and after the introduction of rivaroxaban: A retrospective cohort study. J Bone Joint Surg Br.2011;93:91-95
5Reed AL, Yamazaki H, Kaufman JD, Rubinstein Y, Murphy B, Johnson AC. Molecular cloning and characterization ofa transcription regulator with homology to gc-binding factor. J Biol Chem.1998;273:21594-21602
6Goodall AH, Burns P, Salles I, Macaulay IC, Jones CI, Ardissino D, de Bono B, Bray SL, Deckmyn H, Dudbridge F,Fitzgerald DJ, Garner SF, Gusnanto A, Koch K, Langford C, O'Connor MN, Rice CM, Stemple D, Stephens J, Trip MD,Zwaginga JJ, Samani NJ, Watkins NA, Maguire PB, Ouwehand WH. Transcription profiling in human platelets revealslrrfip1as a novel protein regulating platelet function. Blood.2010;116:4646-4656
7Steele BM, Harper MT, Macaulay IC, Morrell CN, Perez-Tamayo A, Foy M, Habas R, Poole AW, Fitzgerald DJ,Maguire PB. Canonical wnt signaling negatively regulates platelet function. Proc Natl Acad Sci U S A.2009;106:19836-19841
1Ley K. The role of selectins in inflammation and disease. Trends Mol Med.2003;9:263-268
2Frenette PS, Denis CV, Weiss L, Jurk K, Subbarao S, Kehrel B, Hartwig JH, Vestweber D, Wagner DD. P-selectinglycoprotein ligand1(psgl-1) is expressed on platelets and can mediate platelet-endothelial interactions in vivo. J ExpMed.2000;191:1413-1422
3Pabinger I, Ay C. Biomarkers and venous thromboembolism. Arterioscler Thromb Vasc Biol.2009;29:332-336
4Kawabata K, Nagake Y, Shikata K, Fukuda S, Nakazono H, Takahashi M, Ichikawa H, Makino H. Soluble p-selectin isreleased from activated platelets in vivo during hemodialysis. Nephron.1998;78:148-155
5Blann AD, Noteboom WM, Rosendaal FR. Increased soluble p-selectin levels following deep venous thrombosis:Cause or effect? Br J Haematol.2000;108:191-193
6Smith A, Quarmby JW, Collins M, Lockhart SM, Burnand KG. Changes in the levels of soluble adhesion molecules andcoagulation factors in patients with deep vein thrombosis. Thromb Haemost.1999;82:1593-1599
7Myers DD, Jr., Henke PK, Wrobleski SK, Hawley AE, Farris DM, Chapman AM, Knipp BS, Thanaporn P, Schaub RG,Greenfield LJ, Wakefield TW. P-selectin inhibition enhances thrombus resolution and decreases vein wall fibrosis in a ratmodel. J Vasc Surg.2002;36:928-938
8Sullivan VV, Hawley AE, Farris DM, Knipp BS, Varga AJ, Wrobleski SK, Thanapron P, Eagleton MJ, Myers DD,Fowlkes JB, Wakefield TW. Decrease in fibrin content of venous thrombi in selectin-deficient mice. J Surg Res.2003;109:1-7
1Eppihimer MJ, Schaub RG. P-selectin-dependent inhibition of thrombosis during venous stasis. Arterioscler Thromb
2Vasc Biol.2000;20:2483-2488Myers D, Wrobleski S, Londy F, Fex B, Hawley A, Schaub R, Greenfield L, Wakefield T. New and effective treatmentof experimentally induced venous thrombosis with anti-inflammatory rpsgl-ig. Thromb Haemost.2002;87:374-382
3Gremmel T, Ay C, Seidinger D, Pabinger I, Panzer S, Koppensteiner R. Soluble p-selectin, d-dimer, andhigh-sensitivity c-reactive protein after acute deep vein thrombosis of the lower limb. J Vasc Surg.2011;54:48S-55S
4Eichinger S, Minar E, Bialonczyk C, Hirschl M, Quehenberger P, Schneider B, Weltermann A, Wagner O, Kyrle PA.D-dimer levels and risk of recurrent venous thromboembolism. JAMA.2003;290:1071-1074
5Mauriello A, Sangiorgi G, Palmieri G, Virmani R, Holmes DR, Jr., Schwartz RS, Pistolese R, Ippoliti A, Spagnoli LG.Hyperfibrinogenemia is associated with specific histocytological composition and complications of atheroscleroticcarotid plaques in patients affected by transient ischemic attacks. Circulation.2000;101:744-750
6Bates SM. D-dimer assays in diagnosis and management of thrombotic and bleeding disorders. Semin Thromb Hemost.2012;38:673-682
7Kakkar VV, Lawrence D. Hemodynamic and clinical assessment after therapy for acute deep vein thrombosis. Aprospective study. Am J Surg.1985;150:54-63
8Myers DD, Jr., Henke PK, Wrobleski SK, Hawley AE, Farris DM, Chapman AM, Knipp BS, Thanaporn P, Schaub RG,Greenfield LJ, Wakefield TW. P-selectin inhibition enhances thrombus resolution and decreases vein wall fibrosis in a rat
9model. J Vasc Surg.2002;36:928-938Greenfield LJ, Proctor MC. Recurrent thromboembolism in patients with vena cava filters. J Vasc Surg.2001;33:510-514
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