Prevention of thromboembolic events after radical prostatectomy in patients with hereditary thrombophilia due to a factor V Leiden mutation by multidisciplinary coagulation management

Objective:To examine the perioperative impact of factor V Leiden mutation on thromboembolic events'risk in radical prostatectomy(RP)patients.With an incidence of about 5%,factor V Leiden mutation is the most common hereditary hypercoagulability among Caucasians and rarer in Asia.The increased risk of thromboembolic events is three-to seven-fold in heterozygous and to 80-fold in homozygous patients.Methods:Within our prospectively collected database,we analysed 33006 prostate cancer patients treated with RP between December 2001 and December 2020.Of those,patients with factor V Leiden mutation were identified.All patients received individualised recommendation of haemostaseologists for perioperative anticoagulation.Thromboembolic complications(deep vein thrombosis and pulmonary embolism)were assessed during hospital stay,as well as according to patient reported outcomes within the first 3 months after RP.Results:Overall,85(0.3%)patients with known factor V Leiden mutation were identified.Median age was 65(interquartile range:61-68)years.There was at least one thrombosis in 53(62.4%)patients and 31(36.5%)patients had at least one embolic event in their medical history before RP.Within all 85 patients with factor V Leiden mutation,we experienced no thromboembolic complications within the first 3 months after surgery.Conclusion:In our cohort of patients with factor V Leiden mutation,no thromboembolic events were observed after RP with an individualised perioperative coagulation management concept.This may reassure patients with this hereditary condition who are counselled for RP.

Frequency of the C677T Polymorphism of MTHFR, G20210A of Prothrombin and R506Q of Factor V Leiden in Type 2 Diabetics in Abidjan

In Africa, the prevalence of diabetes is escalating and remains a concern due to the numerous complications it causes. Vascular damage associated with diabetes leads to a prothrombotic state observed in diabetic individuals. Diabetes is a complex and multifactorial disease involving genetic components. With the aim of preventing complications and contributing to an efficient management of diabetes, we investigated genes likely to lead to a risk of thrombosis, in particular the C677T of MTHFR, G20210A of prothrombin, and R506Q of factor V Leiden in type 2 diabetics in Abidjan receiving ambulatory care. A descriptive cross-sectional study was carried out on consenting type 2 diabetic patients. Mutation detection was carried out using the PCR-RFLP method employing restriction enzymes. Hemostasis tests (fibrinogen, D-dimers, fibrin monomers, and von Willebrand factor) were performed using citrate tubes on the Stage? Star Max automated system. Plasminogen activator inhibitor was assayed by ELISA method, and biochemical parameters were determined using the COBAS C311. The study population consisted of 45 diabetic patients, 51.1% of whom presented vascular complications, mainly neuropathy. Disturbances in hemostasis parameters were observed, with 15.5% of patients showing an increase in fibrin monomers. Mutation analysis revealed an absence of factor V mutation (factor V Leiden) and of G20210A mutation of the prothrombin gene. However, 15.6% of subjects had a heterozygous C677T mutation of MTHFR, with 57% of them being anemic. The exploration of biological and genetic factors associated with thrombotic risk is of significant interest in the optimal management of African type 2 diabetics.

Mesenteric and portal vein thrombosis associated with hyperhomocysteinemia and heterozygosity for factor V Leiden mutation

A 79-year-old man was hospitalized because of worsening upper abdominal pain which started two days before admission and was continuously present. His personal and family historywas uneventful, he did not smoke and denied toxic habits or using any medications, including overthe-counter medications, herbal remedies or any vitamin supplements.

Prevalence of factor V Leiden and prothrombin G20210A in patients with gastric cancer

AIM： To analyze the prevalence of the two commonest thrombophilic mutations, factor V Leiden and prothrombin G20210A, in patients with gastric cancer. METHODS： One hundred and twenty-one patients with primary gastric carcinoma and 130 healthy subjects, comparable for age and sex, were investigated. Factor V Leiden was detected by using polymerase chain reaction and restriction enzyme digestion, and prothrombin G20210A gene mutation by allele-specific PCR. RESULTS： Among the 121 cancer patients, factor V Leiden was found in 4 cases （GA genotype： 3.3%） and prothrombin G20210A in 10 cases （GA genotype： 8.3%）. Of the 130 control subjects, factor V Leiden was detected in 6 cases （GA genotype： 4.6%） and prothrombin G20210A in 8 cases （GA genotype： 6.1%）. No double heterozygous carriers of both mutations were found in either group. The prevalence of both factor V Leiden and prothrombin G20210A variant was not statistically different between the cancer patients and the healthy subjects. CONCLUSION： Our study suggests that, in gastric cancer, the risk factors of thrombophilic cancer state are on acquired rather than on a genetic basis and that prothrombin G20210A does not seem to be a cofactor in gastric cancer pathogenesis.

Maltose-binding Protein Improving the Crystallizability of C2 Domain of Human Coagulation Factor V

Human coagulation Factor V（FV）, together with Factor Xa, assembles to prothrombinase complex on activated cell surface, which converts prothrombin into thrombin, leading to fibrin deposition. The C2 domain of FV is believed to be a primary anchor for the assembly of pro- thrombinase on the cell surface, and was proposed as a target to intervene with pathological thrombotic events. We report here the crystal structure of the C2 domain of FV fused to maltose-binding protein（MBP）. The fusion tag of MBP is critical to generate the crystal for this study. There is no strong interaction between MBP and FVC2. The overall structure of FVC2 is similar to the previous FVC2 structures, suggesting the MBP fusion does not perturb the molecular structure of FVC2. This crystal form of FVC2 can be used for future study of molecular interaction between FVC2 and its inhibitors.

Effect of Factor V Leiden on Thrombosis in Childhood Leukemia

Thromboembolism is an important complication in children undergoing therapy for ALL as it has the potential to impact adversely on both their survival and quality of life. The incidence of thrombosis in children with ALL varies between 1.1% and 36.7% and the actual mean is 3.2%. The aim of our study is to review the available reported data on the effect of FVL on thrombotic risk in pediatric patients with acute leukemia.

Down Regulated Protein C Plasma Levels in the Absence of Factor V Leiden Mutation in HIV Patients: An Observational Study in Maiduguri, North-Eastern Nigeria

Background: As life expectancy of HIV-infected patients increases with use of highly active antiretroviral therapy (HAART), protean haematologic manifestation including decreased activity of natural anticoagulants such as protein C may occur in the absence of genetic risk factors. Based on this preposition, we assessed the plasma level of protein C, and prevalence of factor V Leiden mutation among HIV-infected individuals. Our cohort consisted of 499 HIV-infected patients, of which 250 had AIDS, while 249 were either asymptomatic or had minor mucocutaneous infection consistent with WHO clinical stages I and II without features of AIDS. We also evaluated 251 healthy, HIV-negative subjects as controls. All participants were tested for plasma protein C levels and factor V Leiden (FVL) mutation (Arg 506 Gln) by automation and amplification created restriction enzyme site (ACRES) polymerase chain reaction, respectively. The prevalence of reduced protein C plasma levels among HIV positive patients was 20%;it was more prevalent among those that had AIDS compared with those without features of AIDS, but within WHO clinical stage I and II, (93.3% vs 6.7%) respectively. None of the control patients had either reduced protein C nor FVL mutation. All participants that demonstrated reduced protein C plasma levels demonstrated normal FVL genotype (1691G/G). Conclusion: Decreased protein C plasma levels can occur in HIV-infected patients in the absence of factor V Leiden mutation. The risk increases with severity of the disease. Deranged protein C plasma level increases the risk of hypercoagulable state in patients with advanced HIV disease;it should be considered among the causes of thrombo embolism in this group of patients.

Are all primary omental infarcts truly idiopathic?Five case reports

BACKGROUND Idiopathic omental infarction(IOI)is challenging to diagnose due to its low incidence and vague symptoms.Its differential diagnosis also poses difficulties because it can mimic many intra-abdominal organ pathologies.Although hypercoagulability and thrombosis are among the causes of omental infarction,venous thromboembolism scanning is rarely performed as an etiological investigation.CASE SUMMARY The medical records of the 5 cases,who had the diagnosis of IOI by computed tomography,were examined.The majority of the patients were male(n=4,80%)and the mean age was 31 years(range:21-38).The patients had no previous abdominal surgery or a history of any chronic disease.The main complaint of all patients was persistent abdominal pain.Omental infarction was detected in all patients with contrast-enhanced computed tomography.Conservative treatment was initially preferred in all patients,but it failed in 1 patient(20%).After discharge,all patients were referred to the hematology department for thrombophilia screening.Only 1 patient applied for thrombophilia screening and was homozygous for methylenetetrahydrofolate reductase(A1298C mutation)and heterozygous for a factor V Leiden mutation.CONCLUSION IOI should be considered in the differential diagnosis in patients presenting with progressive and/or persistent right side abdominal pain.Investigating risk factors such as hypercoagulability in patients with IOI is also important in preventing future conditions related to venous thromboembolism.

15例遗传性凝血因子V缺陷症先证者的临床特征与基因突变分析

目的分析15个遗传性凝血因子V(FV)缺陷症先证者的临床特征与基因突变类型,初步探讨其可能的分子致病机制。方法采用一期凝固法和ELISA法分别检测FV活性(FV:C)和FV抗原(FV:Ag)。用PCR扩增患者F5基因的25个外显子及其侧翼序列,并直接测序。利用蛋白质模型分析其可能的分子机制。结果在5例FV:C大于10%的先证者中,仅有1例出现轻微出血症状;在10例FV:C小于10%的先证者中,7例表现出各种出血症状。15例先证者共检出12个基因突变位点(其中8个为新的突变,1个为致病的多态性)。蛋白质模型分析表明,所有6种错义突变都会导致FV蛋白的构象改变,其中2种(p.Ser1781Arg和p.Asp96His)会减少氢键数量,从而导致局部蛋白质结构不稳定。结论这些遗传性FV缺陷症先证者的FV水平与各自的F5基因突变有关,其FV水平与出血症状具有较强的相关性。

V形斜缺口薄板结构应力场评估方法研究

文中对含有复杂V形倾斜角的薄板结构应力场进行了理论分析和数值研究.通过建立奇异强度因子as与缺口应力强度因子N-SIF的关系,获得无量纲的N-SIF,在此基础上建立一系列不同几何尺寸、张开角与倾斜角下的有限板宽的斜裂纹切口薄板模型,对切口的应力场进行简化与拟合.通过控制变量法得到奇异强度因子与无量纲N-SIF的关系曲线,拟合得到简易的V形倾斜角的薄板结构应力场和N-SIF评估公式.将拟合出的N-SIF简化计算公式和有限元计算结果与传统文献计算结果进行对比与误差分析.结果表明:拟合出的应力场公式精度较高,可实现复杂倾斜角下V形切口应力场的快速评估.

一种40 V NLDMOS器件热载流子寿命研究

为了更精确预测基于0.18μm工艺的40 V NLDMOS器件实际应用条件下的热载流子寿命,介绍了一种通过可靠性测试和计算机辅助数学解析相结合的热载流子可靠性寿命预计方法。该方法基于实际直流状态下的热载流注入测试数据,结合TCAD仿真,对测试结果进行了线性函数、多次函数、幂函数、指数函数及Dreesen R函数拟合;通过分析当前业界LDMOS器件的热载流子注入测试主流模型预测精度的局限性,找出了最优热载流子模型,提出了适合Python语言编程的改进型Dreesen R模型;通过数学解析推导方法以及基于Python语言的计算机辅助编程计算,得出了栅极以及漏极全工作电压范围内的热载流子参数退化曲线;通过模拟工作波形不同上升沿及下降沿的函数曲线、上升及下降时间以及不同占空比,得出随着时间变化的交直流转换因子曲线。最终新的测试项目可以通过不同电压下的直流状态下测试结果以及已经得到的交直流转换因子曲线,来直接获取工作场景交流状态的热载流子寿命。该评估方法解决了采用直流状态下的测试来解决现场复杂应用波形的热载流子寿命评估难题,较大节省了测试时间,提高了寿命预测精度。

Risk assessment of venous thromboembolism in inflammatory bowel disease by inherited risk in a population-based incident cohort

Inflammatory bowel disease(IBD),including Crohn’s disease(CD)and ulcerative colitis(UC),is a chronic inflammatory disease of the digestive tract with increasing prevalence globally.Although venous thromboembolism(VTE)is a major complication in IBD patients,it is often underappreciated with limited tools for risk stratification.AIM To estimate the proportion of VTE among IBD patients and assess genetic risk factors(monogenic and polygenic)for VTE.METHODS Incident VTE was followed for 8465 IBD patients in the UK Biobank(UKB).The associations of VTE with F5 factor V leiden(FVL)mutation,F2 G20210A prothrombin gene mutation(PGM),and polygenic score(PGS003332)were tested using Cox hazards regression analysis,adjusting for age at IBD diagnosis,gender,and genetic background(top 10 principal components).The performance of genetic risk factors for discriminating VTE diagnosis was estimated using the area under the receiver operating characteristic curve(AUC).RESULTS The overall proportion of incident VTE was 4.70%in IBD patients and was similar for CD(4.46%),UC(4.49%),and unclassified(6.42%),and comparable to that of cancer patients(4.66%)who are well-known at increased risk for VTE.Mutation carriers of F5/F2 had a significantly increased risk for VTE compared to non-mutation carriers,hazard ratio(HR)was 1.94,95%confidence interval(CI):1.42-2.65.In contrast,patients with the top PGS decile had a considerably higher risk for VTE compared to those with intermediate scores(middle 8 deciles),HR was 2.06(95%CI:1.57-2.71).The AUC for differentiating VTE diagnosis was 0.64(95%CI:0.61-0.67),0.68(95%CI:0.66-0.71),and 0.69(95%CI:0.66-0.71),respectively,for F5/F2 mutation carriers,PGS,and combined.CONCLUSION Similar to cancer patients,VTE complications are common in IBD patients.PGS provides more informative risk information than F5/F2 mutations(FVL and PGM)for personalized thromboprophylaxis.

Resistance to activated protein C is a risk factor for fibrostenosis in Crohn’s disease

AIM: To evaluate the effect of resistance to activated protein C (aPCR), the most common known inherited thrombophilic disorder, on the risk of intestinal operation of fi brostenosis in patients with Crohn’s disease (CD). METHODS: In a previous study, we assessed the prevalence of aPCR in CD. In a retrospective case- controlled study, 8 of these CD patients with aPCR were now compared with 24 CD patients without aPCR, matched by gender, age at diagnosis and duration of disease in a 1:3 fashion. The primary end point was the occurrence of an intestinal CD-related operation with evidence of fibrostenosis in the bowel resection specimen. RESULTS: The Kaplan-Meier analysis revealed that patients with aPCR had a lower probability of remaining free of operation with f ibrostenosis than patients without aPCR (P = 0.0372; exact log-rank test) resulting in a signifi cantly shorter median time interval from diagnosis of CD to the fi rst operation with fi brostenosis (32 vs 160 mo). At 10 years, the likelihood of remaining free of operation with fi brostenosis was 25% for patients with aPCR and 57.8% for patients without aPCR. CONCLUSION: CD patients with aPCR are at higher risk to undergo intestinal operation of fi brostenosis than those without aPCR. This supports our hypothesis of aPCR being a possible risk factor for fi brostenosis in CD.

两个复合杂合突变导致遗传性凝血因子V缺陷症家系的表型与基因突变分析

目的:对两个由F5基因复合杂合突变导致的遗传性凝血因子V(FV)缺陷症家系进行表型和基因型分析,初步探讨其分子致病机制。方法:检测两个家系各成员外周血的血浆FV活性(FV:C)和FV抗原(FV:Ag)等凝血指标。通过PCR扩增F5基因的所有外显子及其侧翼区域,并进行测序。利用生物信息学软件辅助分析突变对蛋白功能的影响。使用PyMOL软件分析突变前后FV蛋白质的空间结构变化。通过凝血酶生成实验评估突变蛋白的功能变化。结果:表型检测显示两个先证者FV:C和FV:Ag均同步下降,表现为I型FV缺陷症。基因分析显示,先证者A第3外显子存在c.332G>T杂合错义突变(p.Ser111Ile)及第25外显子存在c.6665A>G杂合多态性(p.Arg2222Gly);先证者B第3外显子存在c.286G>C杂合错义突变(p.Asp96His)及第13外显子存在c.2393-2393del C杂合缺失突变(p.Pro798Leufs*13)。生物信息学分析显示,p.Ser111Ile和p.Pro798Leufs*13突变均为致病性突变。蛋白模型分析显示,p.Ser111Ile突变导致氨基酸间的氢键发生改变;p.Pro798Leufs*13突变产生了截断蛋白。凝血酶生成实验表明,先证者A和B的凝血功能已受到影响。结论:这四种突变可能是造成该两个家系FV水平下降的主要原因,其中p.Ser111Ile突变鲜见报道。

平面V型缺口尖端应力强度因子确定的广义参数有限元法

针对工程结构中存在的V型缺口在外荷载作用下容易发生断裂的现象,基于广义参数有限元法和V型缺口尖端Williams级数位移场推导建立了V型缺口应力强度因子(stress intensity factors,SIFs)分析的Williams单元(简记W单元),通过求解整体控制方程,将相应的特征值和广义参数直接代入公式即可获得较高精度的SIFs。结合边界V型缺口算例研究表明:W单元对相对奇异区尺寸和网格加密均不敏感,对W单元的3个重要参数径向离散因子α、径向离散单元数n、级数截取项数m,建议取m=10,α=0.9,n=100,其结果收敛并具有较高的计算精度,且与裂纹研究中给定的建议值相同。通过对非中心缺口不同位置和角度进行算例分析验证了W单元具有高精性,同时参数取值具有通用性。

圆棒试样V型槽超声滚压装置设计及试验研究

设计一种针对圆棒试样V型槽的超声滚压装置,分别对滚压装置及其配套的固定装置、工件夹具等进行了结构设计,利用ANSYS Workbench对装置进行了模态分析和谐响应分析,结果表明装置的共振频率与超声波发生器频率一致,装置能够正常工作。设计单因素试验,探究了不同静压力、超声振幅和滚压遍数等超声滚压工艺参数对渗碳淬火态18CrNiMo7-6合金钢V型槽表面质量的影响。超声滚压加工后试样V型槽底部的表面粗糙度从0.8μm可降至0.141μm;表层残余应力与表面硬度显著提升,滚压过后试样表面最大残余应力为-703.2 MPa,最大硬度可达985.34 HV,较原始表面硬度提高了97.5%。结果表明,采用该装置能够对V型槽底进行超声滚压加工,经超声滚压后,V型槽底部表面质量得到显著提高。

Uncoupling neurotrophic function from nociception of nerve growth factor: what can be learned from a rare human disease?

Nerve growth factor(NGF) is a powerful trophic factor that provides essential support for the survival and differentiation of sympathetic and sensory neurons during development. However, NGF also activates nociceptors contributing significantly to inflammatory pain and neuropathic pain after tissue injury. As such anti-NGF based therapies represent a promising strategy for pain management. Because of dose-dependent serious side effects such as back pain, injection site hyperalgesia, clinical trials of using NGF to treat various disorders such as diabetic neuropathies, chemotherapy-induced and human immunodeficiency virus-associated peripheral neuropathies were all discontinued. Thus far, worldwide clinical applications of NGF in treating patients are very limited except in China. Hereditary sensory autonomic neuropathy type V(HSAN V) is an extremely rare disease. Genetic analyses have revealed that HSAN V is associated with autosomal recessive mutations in NGF. One of the mutations occurred at the 100^(th) position of mature NGF resulting in a change of residue from arginine to tryptophan(R100W). Although those HSAN V patients associated with the NGF^(R100W) mutation suffer from severe loss of deep pain, bone fractures and joint destruction, interestingly patients with the NGF^(R100W) mutation do not show apparent cognitive deficits, suggesting important trophic support function is preserved. We believe that NGF^(R100W) provides an ideal tool to uncouple the two important functions of NGF: trophic versus nociceptive. Studies from investigators including ourselves have indeed confirmed in animal testing that the NGF^(R100W) no longer induced pain. More importantly, the trophic function seemed to be largely preserved in NGF harboring the R100W mutation. On the mechanistic level, we found that the NGF^(R100W) mutation was capable of binding to and signaling through the tyrosine receptor kinase A receptor. But its ability to bind to and activate the 75 kDa neurotrophic factor was significantly diminished. The significance of these findings is at least two folds: 1) the NGF^(R100W) mutation can be used as an alternative to the wildtype NGF to treat human conditions without eliciting pain; and 2) the 75 kDa neurotrophic factor may serve as a novel target for pain management. We will discuss all the details in this mini-review.

METHOD TO CALCULATE STRESS INTENSITY FACTOR OF V-NOTCH IN BI-MATERIALS

Based on Zak＇s stress function, the eigen-equation of stress singularity ofbi-materials with a V-notch was obtained. A new definition of stress intensity factor for a perpendicular interfacial V-notch of bi-material was put forward. The effects of shear modulus and Poisson＇s ratio of the matrix material and attaching material on eigen-values were analyzed. A generalized expression for calculating/（i of the perpendicular V-notch of bi-materials was obtained by means of stress extrapolation. Effects of notch depth, notch angle and Poisson＇s ratio of materials on the singular stress field near the tip of the V-notch were analyzed systematically with numerical simulations. As an example, a finite plate with double edge notches under uniaxial uniform tension was calculated by the method presented and the influence of the notch angle and Poisson＇s ratio on the stress singularity near the tip of notch was obtained.

Lung adenocarcinoma harboring rare epidermal growth factor receptor L858R and V834L mutations treated with icotinib:A case report

BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine-kinase inhibitors are widely used for the treatment of non-small-cell lung cancer with EGFR mutations.However,patients with rare,even compound EGFR mutations have different responses to EGFR-tyrosine-kinase inhibitors,which bring uncertainty to clinical treatment.CASE SUMMARY A 45-year-old female patient presented with a 3-mo history of cough and white sputum without chest pain.Chest computed tomography revealed lung spaceoccupying lesions and multiple lymphadenectasis.Bronchoscopy and pathology suggested lung adenocarcinoma.Compound variation of EGFR gene(exon 21 L858 R/V834 L)was detected in both tissue and circulating tumor deoxyribonucleic acid samples.As a result of next-generation sequencing and her family’s wishes,the patient was given oral treatment with icotinib hydrochloride(125 mg/d,tid)from March 21,2019 and has achieved stable disease for the last 1 year.CONCLUSION Non-small cell lung adenocarcinoma with EGFR L858 R/V834 L was treated successfully with icotinib,and it may be a new medication treatment option.

Factors Affecting the Relation of Fracture Toughness V_(GC) with Critical Void Growth Ratio R_C/R_O

The relationship between fracture toughness VGC and critical void growth RC/RO was studied for ten kinds of Steel. The macroscopic fracture toughness VGC was determined by using notched tensile specimens. and the microscopic parameters of critical void growth ratio RC/RO were quantitatively measured under SEM. Then, the coefhcient C in the relation VGC = C In(RC/RO) proposed in author's past work was specifically explored. The correlation of C with tensile proderty parameter φ=σyδ/(Eφn) was presented for the Steel investigated, and the effects of low temperature on C were also discussed. Results show that the coefficient C is linearly related to the parameter and insensitive to low temperature.