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1865年法国Armand Trousseau教授首次报道静脉血栓与肿瘤之间存在联系,这可能是人们对易栓症(thrombo-phlilia)的最早认识。易栓症不是单一疾病,而是指由于抗凝蛋白、凝血因子、纤溶蛋白等的遗传性或获得性缺陷或存在获得性危险因素而容易发生血栓栓塞的疾病或状态。易栓症的血栓栓塞类型主要为静脉血栓栓塞[1-2]。1易栓症分类易栓症分为遗传性易栓症和获得性易栓症两类[1-2],见表1。常见的遗传性易栓症有蛋白C(PC)缺陷症、蛋白S(PS)缺陷症、抗凝血酶(AT)缺陷症、因子ⅤLeiden(FⅤLeiden)和凝血酶原20210A突变等,是基因缺陷导致相应蛋…     

易栓症检测在静脉血栓栓塞症中的应用进展

<正>静脉血栓栓塞症(venous thromboembolism,VTE)是一种多因素疾病,主要包括深静脉血栓形成(deep vein thrombosis,DVT)和肺血栓栓塞症(pulmonary thromboembolism,PTE),其危险因素包括遗传性和获得性两方面。易栓症指存在抗凝蛋白、凝血因子、纤溶蛋白等遗传性或获得性缺陷,或者存在获得性危险因素而具有高血栓栓塞倾向~([1])。易栓症检测实用性的讨论是静脉血栓领域的     

肺血栓栓塞症患者外周血单个核细胞基因差异表达初探

研究发现，与白种人群静脉血栓形成和肺血栓栓塞密切相关的主要遗传易感因素有活化蛋白C抵抗、凝血因子VLeiden突变、亚甲基四氢叶酸还原酶基因677位点C→T突变以及凝血酶原20210位点G→A多态等。但影响白种人群静脉血栓形成和肺血栓栓塞的主要遗传缺陷在非洲人群、日本、中国香港和台湾人中均很少见，提示血栓倾向存在着人种的遗传异质性，也提示静脉血栓形成和肺血栓栓塞是一种多因素、多基因遗传性疾病。本实验目的是通过病例对照研究探讨与肺血栓栓塞相关的基因表达特征，为深入研究提供证据。     

遗传性易栓症引发急性肺栓塞一例报道

易栓症指各种遗传性或获得性因素导致机体容易发生血栓形成和血栓栓塞的病理状态,是青少年猝死的重要原因之一。易栓症相关血栓事件主要由遗传因素、获得性因素或两者共同引起。本文报道1例遗传性易栓症引发急性肺栓塞患者的诊疗经过,以期为遗传性易栓症的临床诊治工作提供参考。     

肺血栓栓塞和遗传性抗凝血酶缺陷相关性研究进展

抗凝血酶属丝氨酸蛋白酶抑制物超家族成员,是体内凝血酶等的主要抑制物.抗凝血酶基因缺陷会导致抗凝血酶血浆蛋白水平降低,而抗凝血酶缺乏是静脉血栓形成的主要危险性遗传因素之一,因此有必要通过研究肺血栓栓塞症与遗传性抗凝血酶缺陷的关系,找到新的用来作为预测血栓形成或检测高凝状态的生物学指标,并且诊断可能发生肺血栓栓塞症等易栓症的高危人群,从而实现早期预防和个体化治疗策略以及降低发病率和病死率.     

22例易栓症患者的护理

易栓症是指由于遗传性或获得性危险因素导致机体容易发生血栓的病理状态,即凝血因子,纤溶蛋白、抗凝蛋白等遗传或获得性缺陷导致机体容易发生血栓的疾病状态。2010年6月～2011年6月,我们共收治易栓症患者22例。现将护理方法介绍如下。护理：①饮食护理：指导患者减少每日膳食中总的脂肪量,增加多不饱和脂肪酸,以降低血黏度;适量增加蛋白质的     

复合因素导致的获得性易栓症肝素1例

易栓症(thrombophilia)最早在1965年由Egeberg在报道一个家族性抗凝血酶缺陷时首次提出[1].目前易栓症分为遗传性与获得性两类,是指存在抗凝蛋白、凝血因子、纤溶蛋白等遗传性或获得性缺陷,或者存在获得性危险因素而具有高血栓栓塞倾向[2].获得性易栓症最常见的原因为抗磷脂抗体综合征(antiphospholipid antibody syndrome,APS),其治疗主要为抗凝治疗.直接口服抗凝剂(direct oral anticoagulants,DOACs)如达比加群酯、利伐沙班等已广泛用于下肢深静脉血栓及心房颤动患者的脑栓塞防治中,但对于APS患者的治疗,尚缺乏大型研究验证其疗效及安全性证据[3].本文报道一例复合因素导致的获得性易栓症病例,分析其脑梗死治疗经过,对比DOACs与低分子肝素的疗效.临床资料患者女性,60岁,5 d前突然出现言语困难,表现为找词困难.     

第492例——反复血栓形成, 血小板减低

患者女性, 43岁。因反复血栓形成2年余, 血小板(PLT)减低1年余就诊。患者临床表现为反复动静脉血栓形成、少见部位血栓及抗凝治疗中新发血栓, 伴有进行性加重的血小板减少。外院及我院多次筛查抗核抗体、抗可溶性抗原抗体、抗磷脂抗体谱均为阴性。病程中糖皮质激素冲击及静脉免疫球蛋白(IVIG)曾使血小板升至正常, 骨髓巨核细胞成熟障碍, 支持免疫性血小板减低。入院后筛查易栓症的病因, 同时予肝素静脉泵入抗凝, 利妥昔单抗600 mg 1次;IVIG 20 g/d×3 d;口服艾曲波帕50 mg/d治疗。以上治疗3周后, 血小板减少无明显改善, 期间仍有新发血栓。后易栓症基因筛查回报PROS1基因杂合突变, MTHFR基因型为TT型, 发现少量IgGκ型M蛋白, 但仍不足以解释如此顽固的血栓倾向。在排除肿瘤、肝素诱导的血小板减少症等之后最终诊断血清阴性抗磷脂综合征可能性大。后续加用地塞米松20 mg/d×4 d, 联合口服西罗莫司2 mg/d加强免疫抑制, 抗凝方案过渡为低分子肝素后出院。1个月后电话随访, 患者颅内静脉窦血栓所致的头痛症状好转, PLT升至(20～30)×109/L, 无新...     

蛋白C、蛋白S缺乏与肺血栓栓塞症的相关性研究进展

肺血栓栓塞症临床症状不典型,使其诊断困难,漏诊率、误诊率及病死率高,掌握高危因素对提高诊断率及合理治疗具有重要意义.对于复发性、家族性肺血栓栓塞症患者,可能存在遗传性高危因素.蛋白C、蛋白S属蛋白C系统,具有抗凝作用,其缺乏是肺血栓栓塞症的重要遗传性危险因素.掌握蛋白C、蛋白S缺乏与肺血栓栓塞症的相关性对于指导合理治疗、降低复发率及病死率具有重要意义.     

肺血栓栓塞症患者易栓症的分析研究

目的:探讨我国肺血栓栓塞症(PTE)患者易栓症的发生率,以提高临床PTE的诊断与预防复发的水平。方法:自2004年2月至2009年12月,连续观察我院呼吸科、急诊呼吸监护室确诊的PTE患者123例,其中男性60例,女性63例,并对其遗传性和获得性易栓症进行回顾性分析,得出所有患者遗传性和获得性易栓症的发生率,并比较性别对抗凝蛋白缺陷的影响。结果:123例PTE患者中获得性易栓症中长期制动、静脉曲张/血栓性静脉炎及手术/创伤居前3位,其发生率分别为14.6%、12.2%及8.1%。遗传性易栓症总的发生率为:55.3%,其中发生率较高的是:蛋白S(PS)缺陷17.1%,PC缺陷10.5%,蛋白C(PC)、PS联合缺陷12.2%。抗凝蛋白缺陷男女均为34例,性别间差异无统计学意义(P0.05)。抗凝蛋白缺陷率性别间差异无统计学意义。结论:PTE患者中易栓症的发生率较高,PTE可能是遗传性和获得性易栓症共同作用的结果。     

The investigation and management of inherited thrombophilia

Inherited thrombophilia can be defined as a genetically determined tendency to venous thromboembolism. Genetic risk factors for venous thrombosis include antithrombin deficiency, protein C deficiency, protein S deficiency, activated protein C resistance due to the factor V gene Leiden mutation, inherited hyperhomocysteinaemia, elevated factor VIII levels and the prothrombin gene G20210 A variant. A genetic risk factor is now identifiable in up to 50% of unselected patients with venous thrombosis. Individuals with inherited thrombophilia may develop venous thrombosis at a young age, or they may present with thrombosis at an unusual site or in the apparent absence of any precipitating event. A family history of thrombosis is suggestive of inherited thrombophilia. Laboratory investigations for inherited thrombophilia should include testing for activated protein C resistance and the factor V gene Leiden mutation, and screening for deficiencies of antithrombin, protein C or protein S. Screening for the prothrombin gene G20210 A variant, and measurement of plasma factor VIII and homocysteine levels should be considered in individual cases. In recent years the multifactorial nature of thrombophilia, both circumstantially and on a genetic level, has become increasingly apparent. Individuals with more than one inherited thrombophilia risk factor are particularly prone to thrombosis and their identification is a priority.     

Risk of thrombosis associated with oral contraceptives of women from 97 families with inherited thrombophilia: high risk of thrombosis in carriers of the G20210A mutation of the prothrombin gene

BACKGROUND AND OBJECTIVES: Oral contraceptives (OC) and inherited thrombophilia are well-known risk factors associated with venous thromboembolism (VTE). However, there are only few studies on the risk of VTE in women with inherited thrombophilia who use oral contraceptives. DESIGN AND METHODS: We performed a retrospective family cohort study of 325 women belonging to 97 families with inherited thrombophilia, including antithrombin, protein S and C deficiencies, the factor V Leiden mutation (FVL) and the G20210A mutation of the prothrombin gene (PT20210A) to determine the risk of VTE associated with OC intake. RESULTS: For carriers of the PT20210A mutation, the risk of VTE in OC users was 3-fold higher (95% CI 1.3-6.8) than that in non-carriers. Carriers of FVL mutation taking OC showed an OR of 1.4 (95% CI 0.6-3.3), indicating a tendency to increase the risk of VTE. INTERPRETATION AND CONCLUSIONS: Because of the high prevalence of the PT20210A (6.5%) and FVL (2%) mutations in the general Spanish population and the increased risk of VTE associated with OC intake, genetic screening for these mutations should be considered in potential OC users belonging to families with thrombophilia.     

Gene-gene and gene-environment interactions determine risk of thrombosis in families with inherited antithrombin deficiency.

To analyze inherited antithrombin deficiency as a risk factor for venous thromboembolism in various conditions with regard to the presence or absence of additional genetic or acquired risk factors, we compared 48 antithrombin-deficient individuals with 44 nondeficient individuals of 14 selected families with inherited antithrombin deficiency. The incidence of venous thromboembolism for antithrombin deficient individuals was 20 times higher than among nondeficient individuals (1.1% v 0.05% per year). At the age of 50 years, greater than 50% of antithrombin-deficient individuals had experienced thrombosis compared with 5% of nondeficient individuals. Additional genetic risk factors, Factor V Leiden and PT20210A, were found in more than half of these selected families. The effect of exposure to 2 genetic defects was a 5-fold increased incidence (4.6% per year; 95% confidence interval [CI], 1.9% to 11.1%). Acquired risk factors were often present, determining the onset of thrombosis. The incidence among those with exposure to antithrombin deficiency and an acquired risk factor was increased 20-fold (20.3% per year; 95% CI, 12.0% to 34.3%). In conclusion, in these thrombophilia families, the genetic and environmental factors interact to bring about venous thrombosis. Inherited antithrombin deficiency proves to be a prominent risk factor for venous thromboembolism. The increased risks among those with exposure to acquired risk factors should be considered and adequate prophylactic anticoagulant therapy in high-risk situations seems indicated in selected families with inherited antithrombin deficiency.     

Thromboembolism in children

Acquired and inherited prothrombotic risk factors increase the risk of thrombosis in children. This review is based on "milestone" pediatric reports and new literature data (January 2001-February 2002) on the presence of acquired and inherited prothrombotic risk factors, imaging methods, and treatment modalities in pediatric thromboembolism. After confirming clinically suspected thromboembolism with suitable imaging methods, pediatric patients should be screened for common gene mutations (factor V G1691A, prothrombin G20210A and MTHFR C677T genotypes), rare genetic deficiencies (protein C, protein S, antithrombin, and plasminogen), and new candidates for genetic thrombophilia causing elevated levels of lipoprotein(a), and homocysteine, and probable genetic risk factors (elevations in fibrinogen, factor IX, and factor VIIIC, and decreases in factor XII). Data interpretation is based on age-dependent reference ranges or the identification of causative gene mutations/polymorphisms with respect to individual ethnic backgrounds. Pediatric treatment protocols for acute thromboembolism, including thrombolytic and anticoagulant therapy, are mainly adapted from adult patient protocols.     

Who should be tested for thrombophilia?

PURPOSE OF REVIEW: The purpose of this review is to identify on the basis of available data and expert opinions who would benefit most from screening for thrombophilia. RECENT FINDINGS: Recent studies have clearly defined the risk of venous thromboembolism in members of families with inherited thrombophilia. Meta-analyses have shown the role of the most common thrombophilic conditions in increasing the risk of recurrent venous thromboembolism in carriers. Screening for thrombophilia in venous thromboembolism patients might help identify those at higher risk of recurrences even though it is unclear how this information can be of use in modifying their management. Thrombophilia seems to play a role in early fetal losses as also shown in women at their first intended pregnancy, which makes it interesting to screen women after only one bad pregnancy outcome. SUMMARY: Screening for thrombophilia can be performed particularly in young patients with venous thromboembolism. Carriers of inherited thrombophilia are at increased risk of venous thromboembolism recurrences. Screening families of venous thromboembolism patients with thrombophilia allows the identification of still asymptomatic carriers who may benefit from thromboprophylaxis. This may be true of women in fertile age belonging to thrombophilic families. In thrombophilic women with pregnancy complications prophylaxis may be offered to prevent recurrences.     

Perinatal aspects of inherited thrombophilia

The identified main causes of inherited thrombophilia are deficiencies of antithrombin, protein C and protein S, activated protein C (APC) resistance and the factor V Leiden mutation, mutant factor II, and inherited hyperhomocysteinemia. In women from symptomatic families these defects may be associated with an increased risk of venous thrombosis in pregnancy and recurrent fetal loss. Inherited thrombophilia is common and appears to be a multigene disorder. The thrombotic risk would seem to be greatest in women with antithrombin deficiency and more than one thrombophilia defect. The abnormalities that are now recognized represent only part of the genetic predisposition to thrombosis. In assessing thrombotic risk in pregnancy, acquired risk factors as well as genetic predisposition should be considered. Increasing age, obesity, immobility, and delivery by cesarean section are major risk factors. Pregnancy should be planned, and each patient should be managed on an individual basis. In pregnancy, heparin is the anticoagulant of choice, and as far as possible, treatment with warfarin should be avoided because of the risks to the fetus. When patients are on long-term treatment with warfarin, pregnancy should be avoided, and warfarin should be discontinued prior to embarking on a pregnancy or as soon as pregnancy is suspected and before 6 weeks' gestation. In women from symptomatic families with antithrombin deficiency, adjusted dose heparin throughout pregnancy is recommended and warfarin for at least 3 months post partum. In protein C and protein S deficiency, factor V Leiden, or mutant factor II, treatment can be based on personal and family history. Thromboprophylaxis in late pregnancy and post partum should be considered. Fetal loss may be increased in women with inherited thrombophilia. The risk appears greatest in women with antithrombin deficiency and women with more than one thrombophilia defect. A number of reports have claimed that prophylactic treatment with heparin during pregnancy has resulted in successful pregnancy in women with recurrent fetal death and inherited thrombophilia.     

Inherited factors in thrombosis

Patients with inherited defects or abnormalities that impair the naturally-occurring anticoagulant and fibrinolytic systems are at risk of developing venous and, more rarely, arterial thromboembolism. The prevalence of inherited thrombophilia in the general population is higher than that of inherited bleeding disorders (ca. 1 in 7500 vs 1 in 20,000). Low levels or dysfunctional forms of antithrombin III, protein C and protein S and abnormal fibrinogens are the most frequent and well-established inherited causes for thrombosis. Less frequent and/or less established causes are low heparin cofactor II and plasminogen and high levels of plasminogen activator inhibitor and histidine-rich glycoprotein. The pathophysiology, genetic and clinical aspects and laboratory diagnosis of inherited thrombotic disorders are reviewed and an approach to prophylaxis and therapy is outlined.     

Screening for inherited thrombophilia: indications and therapeutic implications

BACKGROUND AND OBJECTIVES: In recent years knowledge concerning inherited and acquired causes of thrombophilia has increased greatly. The most common inherited traits (deficiency in antithrombin, protein C, or protein S, factor V Leiden, prothrombin G20210A) and mild hyperhomocysteinemia are diagnosed in at least 40% of patients with venous thromboembolism (VTE). INFORMATION SOURCES: The authors work in this field, contributing to multicenter clinical and laboratory investigations and to peer-reviewed journals with original papers. The material examined in this review includes articles published in journals covered by MedLine. STATE OF THE ART: The associated risk for VTE is different according to genotype, being higher among the carriers of natural anticoagulant deficiencies and homozygotes for factor V Leiden. The overall prevalence of thrombophilic traits in the general population being near to 10% renders the probability of carrying multiple defects not excessively rare, with a further increase in thrombotic risk of up to 20-fold. Thus, clinical penetrance is heterogeneous, producing either mild or severe venous thrombotic manifestations, which can be unprovoked or associated with circumstantial risk factors and occur in either young or advanced age. More recently, inherited thrombophilia has been focused on as an important determinant of complications of pregnancy and puerperium. As expected, inherited thrombophilia produces an increased risk of VTE, particularly during puerperium. Moreover it is well established that thrombophilic women have an increased risk of late and/or recurrent fetal loss; whether they are at higher risk of pre-eclampsia, fetal growth restriction, and abruptio placentae is debated. Overall, 40% of women with obstetric complications other than VTE carry a thrombophilic trait. Yet, as a rule VTE and obstetric complications seem to occur in different individuals, probably because of the presence of unknown factors favoring one or other of these clinical manifestations. CONCLUSIONS AND PERSPECTIVES: Inherited thrombophilia is now viewed as a multicausal model, the clinical event being the result of gene-gene and gene-environment age-dependent interactions; the associated clinical manifestations can be heterogenous as regards severity as well as type of event (VTE or obstetric complication). Therefore the criteria for screening affected individuals who have suffered from the above complications or their relatives should not be very stringent. The patient's genotype could be a main determinant of the features of primary or secondary prophylaxis used in the affected individual.     

Coinheritance of the HR2 haplotype in the factor V gene confers an increased risk of venous thromboembolism to carriers of factor V R506Q (factor V Leiden).

With the aim of establishing whether the HR2 haplotype in factor V affects the risk of venous thromboembolism, a retrospective multicenter cohort study was performed in 810 family members identified through 174 probands who suffered from at least 1 episode of deep vein thrombosis and/or pulmonary embolism and had an inherited defect associated with thrombophilia (antithrombin, protein C, or protein S deficiency; factor V R506Q or prothrombin G20210A). Fifty-eight percent (468/810) of the family members had an inherited defect and 10% (47/468) were symptomatic. The HR2 haplotype was found in association with factor V R506Q more frequently in family members with venous thromboembolism (18%) than in those without (8%). Double heterozygosity for factor V R506Q and HR2 conferred a 3- to 4-fold increase in the relative risk of venous thromboembolism compared with factor V R506Q alone. The median age at first event was lower when the 2 defects were associated (46 v 52 years). No increase in risk of venous thromboembolism could be demonstrated when the HR2 haplotype was associated with inherited thrombophilic defects other than factor V R506Q. Because both factor V R506Q and the HR2 haplotype are very frequent, the effect of their coinheritance on the risk of venous thromboembolism might represent a clinically relevant issue, and screening for HR2 in carriers of factor V R506Q should be considered.     

Antithrombotic prophylaxis and treatment in thrombophilic disorders in gynaecology and obstetrics

Pregnancy and puerperium are physiological thrombophilic condition and risk of venous thromboembolism in pregnancy is 4 - 6 fold higher. This risk is further increased in the presence of the additional risk factors. Inherited thrombophilia is well-defined risk factor for VTE in pregnancy and also can be the risk for obstetrics complications. So that early diagnostic of inherited thrombophilia can result in the decrease of risk of VTE and the obstetrics complications.