遗传性抗凝蛋白缺陷症与静脉血栓关系的研究进展

抗凝蛋白缺陷症是静脉血栓栓塞症发病的主要危险因素之一。抗凝蛋白缺陷症分为遗传性和获得性两种，其中遗传性抗凝蛋白缺陷症主要是由蛋白C（PC）、蛋白S（PS）和抗凝血酶（AT）缺陷症导致。PC、PS和AT缺陷症在静脉血栓发病中所占的比率分别为2．0％～8．0％、7．3％和1．0％～8．0％；不同抗凝蛋白缺陷所导致的临床症状差别不大，但AT缺陷症的临床表现最为严重。     

六例遗传性易栓症的血栓发生与实验表型及基因型关联分析

易栓症包括遗传性和获得性.获得性易栓症继发于手术创伤、制动、口服避孕药、母体免疫性疾病、恶性肿瘤等,遗传性易栓症主要是由蛋白C(PC)、蛋白S(PS)和抗凝血酶(AT)缺陷导致.AT缺陷的发病率为1/5000～1/500,病情较为严重.遗传性PC缺陷为常染色体显性遗传病,杂合子型PC缺陷症患者多在30～40岁发病,有很大一部分杂合子型不发病,纯合子和复合杂合较罕见.PS缺陷为常染色体显性遗传,杂合子型60％ ～ 80％患有深静脉血栓(VTE),发病年龄多在40～45岁[1].本研究对我院2010至2012年收治的6例AT、PC和PS缺陷的患者及其家系进行血栓发生及相关研究.     

住院糖尿病患者中恶性肿瘤患病状况的调查

目的：调查住院糖尿病患者恶性肿瘤的患病状况及其危险因素。方法回顾性分析南方医科大学附属南海医院4632例住院糖尿病患者的临床资料,统计出恶性肿瘤的患病及分布情况;分别按糖尿病病程及糖尿病血糖控制情况进行分层,对比分析其恶性肿瘤患病率的差异;对糖尿病患者恶性肿瘤患病的危险因素进行多因素分析。结果住院糖尿病患者,恶性肿瘤的检出率为7．82％,其中前3位为肠癌、肺癌、肝癌分别占20．71％、18．78％、15．19％;患病高峰年龄在50-70岁,占65．76％。血糖控制不达标患者恶性肿瘤患病率高（P ＜0．05）,糖尿病病程10年以上者恶性肿瘤的患病率高（P ＜0．05）。多因素非条件 logistic 回归分析示年龄、性别、吸烟、糖尿病长病程、血糖控制不达标患者发生恶性肿瘤的 OR（95％CI）分别为1．854（1．343～3．922）、1．791（1．138～3．664）、1．989（1．232～3．823）、1.826（1．312～4．126）、1．925（1．435～4．306）。结论住院的糖尿病患者恶性肿瘤的患病率较高,高龄、男性、吸烟、糖尿病长病程及血糖控制不达标是糖尿病患者发生恶性肿瘤的危险因素。     

基于简易评分表危险因素分析对妇科盆腔手术患者术后静脉血栓栓塞症的预防效果

目的 探讨基于简易评分表的危险因素分析对妇科盆腔手术患者术后静脉血栓栓塞症（VTE）的预防效果。方法 选取 2019 年 1 月至 2022 年 12 月邢台市人民医院收治并行妇科盆腔手术后 VTE 患者 102 例作为研究组，同时选取同期行妇科盆腔手术后 未发生 VTE 患者 204 例作为对照组。根据相关指标制定简易评分表，探讨基于简易评分表的妇科盆腔术后 VTE 的影响因素及 预防效果。结果 单因素分析显示，患者年龄、静脉曲张、合并症及术后卧床时间是发生术后 VTE 的危险因素，多因素分析显 示，年龄（>55 岁）、静脉曲张（有）、合并症（有）和术后卧床时间（≥120h）是诱发术后 VTE 的独立危险因素。研究组术后 VTE 持续时间短于对照组，VTE 二次复发率低于对照组（P<0.05）。结论 静脉血栓栓塞症作为妇科盆腔手术术后常见并发症， 年龄、静脉曲张、合并症和术后卧床时间是诱发病症的独立危险因素     

基于Apriori关联规则的急诊危重病人静脉血栓栓塞症现状分析

目的:分析急诊危重病人静脉血栓栓塞症（VTE）的危险因素，为制订适用急诊室病人的VTE早期识别模型及评估方法提供参考。方法:回顾性分析浙江省某三级甲等医院急诊室203例VTE病人的临床资料，通过Apriori算法挖掘分析相关危险因素间的关联规则。结果:203例VTE病人中单纯深静脉血栓形成（DVT）占比（63.0%）最高，单纯肺血栓栓塞症（PTE）次之，DVT合并PTE占比（16.3%）最低；关联结果显示，急诊室病人中的前8项VTE危险因素条目依次为创伤和/或手术（<1个月）、糖尿病史、卧床>72 h、下肢肿胀、恶性肿瘤、年龄≥60岁、高血压史及体质指数为18.5～25.0 kg/m2。结论:基于Apriori关联规则分析急诊危重病人VTE发生的危险因素，可为进一步建立符合急诊室危重病人的VTE早期预测模型提供参考。     

2003－2013年1136例静脉血栓栓塞症住院患者临床资料分析

目的:了解静脉血栓栓塞症(VTE)住院患者的临床资料,为VTE防治提供临床参考。方法:对南通大学附属医院11年间确诊的VTE住院患者临床资料进行回顾性分析。结果:共收治1 136例VTE患者,男女比例为1∶1。发病年龄16~99岁。VTE平均年构成比0.22%。VTE构成比随年龄增加而上升。排名前三的危险因素有制动(35.6%)、手术史(26.7%)、外伤史(17.8%)。872例(86%)DVT采用彩色多普勒超声确诊,167例(98.2%)PTE采用超声心动图联合胸部增强CT确诊。平均住院费用2.65万元。结论:VTE是由多种危险因素导致的潜在致死性疾病,临床表现不典型,需尽早使用辅助诊断技术,加强预防,降低发病率。     

血栓性疾病患者抗凝蛋白检测的临床意义

目的 探讨血栓性疾病患者蛋白C(PC)、蛋白S(PS)和抗凝血酶(AT)活性水平检测在排除常见获得性血栓危险因素中的临床意义.方法 检测85例血栓性疾病患者与50名正常健康对照者血浆PC、PS、AT活性水平,并作比较分析.结果 85例血栓性疾病患者中位年龄42(17～69)岁.其中≤45岁者60例(70.6%).动脉血栓组和静脉血栓组患者PC、PS、AT活性均明显低于正常对照组(P<0.01);复发组PC、PS、AT平均活性低于初发组(P<0.01);年龄≤45岁患者组PC、PS、AT平均活性低于45岁以上组(P<0.01).共有26例(30.6%)患者存在抗凝蛋白活性降低;PS活性降低的发生率最高(10.6%),其次为PC活性降低(8.2%),AT活性降低和联合活性降低(各占5.9%).结论 无明确常见获得性血栓危险因素的血栓患者发病年龄较轻,且普遍存在抗凝蛋白水平低下;抗凝蛋白活性降低不仅与血栓性疾病的发生有关,而且与血栓复发密切相关.     

探讨反复自然流产的免疫病因学诊断

反复自然流产（Recurrent Spontaneous Abortion，RSA）是一种常见的妊娠并发症。除部分因内分泌、染色体异常及生殖道畸形等因素外，80％以上原因不明。对RSA的免疫病因构成进行归纳分析显示，原发性流产患者中，封闭抗体缺乏者占31．4％；透明带抗体阳性者占20．4％；磷脂抗体阳性者占8．5％；ABO血型抗体阳性者占8．4％，     

重症监护室病人发生静脉血栓栓塞症的危险因素及护理对策

[目的]分析重症监护室（ICU）病人发生静脉血栓栓塞症（VTE）的流行病学资料及高危因素,为临床规范性治疗、预防及护理VTE提供参考依据,从而降低VTE的发生率。[方法]回顾性分析618例ICU病人的临床资料,统计发生VTE病人年龄、性别分布及高危因素,并针对发生VTE的危险因素给予相应的护理对策。[结果]VTE男性的发病率高于女性,发生VTE的年龄高峰主要在60岁～69岁,其次是70岁～79岁;发生VTE危险因素主要包括行动受限、机械通气障碍、年龄偏高、药物使用不当、骨折、血液高凝等。[结论]做好ICU病人发生VTE病人的管理,提高医护人员对PTE的认识,并给予积极治疗、预防及护理可减少ICU病人发生VTE。     

高原地区急性肾功能衰竭临床分析

目的总结高原地区住院的急性肾功能衰竭（ARF）患者病因、临床特点以及影响预后的因素。方法回顾性分析西藏军区总医院2001年5月至2006年4月收治的ARF患者临床资料。结果共收治ARF患者148例，其中男性85例，女性63例，年龄（42．4±18．1）岁；其中医院获得性ARF占52．7％，5年来其所占比率有逐渐增加的趋势。肾前性ARF48例（32．4％），以急性高原病最常见，占20例。肾性ARF90例（60．8％），其中小球及微血管病变24例，急性肾小管坏死53例，急性间质性肾炎12例，单肾肾挫伤1例。由药物导致的肾损害39例，占肾性ARF的43．3％。肾后性10例（6．8％），病因主要为结石。患者总病死率为42．6％，其中的医院获得性ARF患者病死率（55．1％）明显高于社区获得性ARF患者（28．6％）（P〈0．01）；透析治疗与未透析治疗患者的病死率差异无统计学意义（P〉0．05）。单因素分析显示，年龄、少尿或无尿、血尿、血红蛋白和器官衰竭数是影响预后的因素，多因素logistic回归分析显示年龄、器官衰竭数和血红蛋白是影响病死率的因素。结论急性高原病和肾毒性药物导致的ARF在高原ARF患者中多见。医院获得性ARF发病率和病死率明显增加。预防多脏器功能不全综合征的发生是降低ARF病死率的关键。     

Low borderline plasma levels of antithrombin,protein C and protein S are risk factors for venous thromboembolism

Summary. Background: Inherited deficiencies of antithrombin (AT), protein C (PC) and protein S (PS) are risk factors for venous thromboembolism (VTE). They are usually defined by laboratory cut‐offs (in our setting 81, 70 and 63 IU dL^?1, respectively), which give only a rough idea of the VTE risk associated with plasma levels of these proteins. Objectives: We investigated whether the risk of VTE associated with the plasma deficiencies of AT, PC or PS has a dose–response effect, and whether low borderline levels of these proteins are associated with an increased risk of VTE, both in the whole study population and separately in carriers of either factor V Leiden or G20210A prothrombin gene mutation. Patients/Methods: A case–control study of 1401 patients with a first objectively‐documented VTE and 1847 healthy controls has been carried out. Results: A dose–response effect on the VTE risk was observed for all the three anticoagulant proteins. Compared with individuals with AT, PC or PS levels > 100 IU/dL, the adjusted odds ratio (95%CI) of VTE was 2.00 (1.44–2.78) for AT levels between 76 and 85 IUdL^?1, 2.21 (1.54–3.18) and 1.84 (1.31–2.59) for PC and PS levels between 61 and 75 IUdL^?1. The risk of unprovoked VTE in factor V Leiden or prothrombin G20210A carriers appears 2 to 3‐fold increased when levels of AT or PS are low borderline. Conclusions: Low borderline plasma levels of AT, PC and PS are associated with a 2‐fold increased risk of VTE and should be considered in the assessment of the individual VTE risk.     

Recommendations for clinical laboratory testing for protein C deficiency,for the subcommittee on plasma coagulation inhibitors of the ISTH

Inherited protein C (PC) deficiency increases risk of venous thromboembolism (VTE) by 5 to 10‐fold in thrombosis‐prone families; however, heterozygous PC deficiency alone does not determine that a subject has thrombophilia. Protein C deficient subjects, who lack additional inherited risk factors such as factor V Leiden or have no major acquired risk factors, may not suffer from VTE. In addition, PC deficiency may be acquired, often due to vitamin K antagonist treatment or liver disease. In contrast, homozygous or compound heterozygous PC deficiencies are rare and serious disorders, and affected infants are often in families with no history of PC deficiency or thrombosis. Laboratories commonly use the chromogenic PC assay to diagnose deficiency. Chromogenic assay is recommended due to its good specificity, but this assay fails to detect the rare type 2b deficiency where the defect is due to poor interaction with calcium ions, phospholipid, protein S, and factor Va and factor VIIIa. The clotting‐based assay of PC is capable of detecting type 2b deficiency but it has reduced specificity. Importantly, PC level varies with age, adult reference ranges cannot be applied to babies or children and levels may not reach those of adults even in adolescence. Pre‐analytical variables in the specimen affect measurement of PC, and can be assay‐dependent; for example, a partially clotted sample will have falsely raised PC level by chromogenic assay but reduced level by clotting‐based assay. Direct oral anticoagulants falsely raise PC level in the clotting‐based assay but the standard chromogenic assay is unaffected.     

下肢深静脉血栓形成患者抗凝蛋白缺陷的临床研究

目的：研究中国人群下肢深静脉血栓形成（IDVT）患者抗凝蛋白缺陷的发生率，探讨中国人群LDVT的主要发病机制。方法：应用ACLPutLlm型全自动血凝仪检测1幔）例LDVT患者（73例初发，27例复发）和100例健康人的抗凝血酶（AT）、蛋白S（PS）、蛋白C（PC）活性及活化蛋白C抵抗性（APCR）。结果：LDVT组与正常对照组相比、LDVT复发组与初发组相比，AT、PS、PC活性明显降低，APCR阳性率明显升高，均有极显著差异（P〈0．01）；本组100例LDVT患者中共有25例患者存在有抗凝蛋白缺陷，以PS缺陷的总发生率最高，为13％（13例），其次是PC缺陷，为8％（8例）；AT缺陷占5％（5例），APCR缺陷的总发生率最小，为4％（4例）。结论：先天性或获得性抗凝蛋白缺陷是中国人LDVT发病和复发的重要机制之一，因此有必要对LDVT患者进行抗凝蛋白水平的筛选。     

A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S,protein C or antithrombin

See also Keeling D. Thrombophilia screening or screaming. This issue, pp 1191–2. Summary. Background: Absolute risks of venous thromboembolism (VTE) in protein S‐, protein C‐, or antithrombin‐deficient subjects are mainly based on retrospective data. Screening asymptomatic relatives of these patients is disputed, though studies addressing this issue have yet to be conducted. Methods: We prospectively followed 382 relatives of 84 probands. Participants were assessed for other thrombophilic defects and occurrence of exogenous risk factors (i.e. surgery/trauma/immobilization, malignancies, use of systemic estrogens, and pregnancy/puerperium). After screening, deficient subjects were advised to use thromboprophylaxis during exogenous risk factors; use of oral contraceptives was discouraged. Results: Overall annual incidence of VTE was 1.53% (95% CI, 1.00–2.34) in deficient vs. 0.29% (0.13–0.64) in non‐deficient relatives; adjusted hazard ratio, 7.0 (95% CI, 2.7–18.0). Annual incidence of unprovoked VTE was 0.95% in deficient vs. 0.05% in non‐deficient subjects; age‐adjusted hazard ratio, 22.3 (P = 0.003). In contrast, annual incidence of provoked VTE was 0.58% vs. 0.24%; age‐adjusted hazard ratio, 2.8 (P = 0.08). Fifty‐five (37%) deficient and 80 (34%) non‐deficient subjects experienced 91 and 143 exogenous risk factors, respectively, during which six vs. five VTEs (6.6% vs 3.5% per risk‐period) occurred, despite the higher compliance with recommended thromboprophylaxis use in deficient (51%) vs. non‐deficient (22%) subjects. In deficient subjects all provoked VTEs occurred when thromboprophylaxis was not used. Conclusions: Protein S, protein C or antithrombin deficiencies confer high absolute risk of VTE. Screening and subsequent augmentation of thromboprophylaxis use may result in reduction of provoked VTE, whereas risk of unprovoked VTE could not be affected by screening.     

The incidence of venous thromboembolism in carriers of antithrombin, protein C or protein S deficiency associated with the HR2 haplotype of factor V: a family cohort study

In order to assess whether the HR2 haplotype of the factor V gene (HR2) increases the risk of venous thromboembolism (VTE) in carriers of antithrombin (AT), protein C (PC) or S (PS) defects, we performed this determination in 336 subjects, who were family members of 66 symptomatic patients with clotting inhibitors defects. We first assessed the presence of previous VTE, and then followed prospectively subjects without prior VTE. VTE episodes had occurred in 26 individuals: 18 in 139 carriers of clotting inhibitors defects alone (annual incidence, 0.55%), four in 33 carriers of clotting inhibitors defects combined with HR2 (0.52%) and four in 151 non-carriers (0.1%), resulting in a relative risk (RR) for VTE of 4.9 (95% CI: 1.7-14.4) and 4.62 (95% CI: 1.2-18.4), respectively. After an overall follow-up of 2557 patient-years, VTE episodes developed in 12 subjects: nine in 121 carriers of clotting inhibitors defects alone (annual incidence, 0.92%), three in 29 carriers of clotting inhibitors defects combined with HR2 (1.0%) and none in 147 non-carriers. In family members of patients with AT, PC or PS defects the coinheritance of HR2 haplotype does not seem to increase the thromboembolic risk.     

Venous thromboembolism in patients with advanced cancer under palliative care: additional risk factors, primary/secondary prophylaxis and complications observed under normal clinical practice

We analyzed the principal risk factors of venous thromboembolism (VTE) (immobilization, recent surgery and previous VTE), prophylaxis with low-molecular weight heparin (LMWH) and complications (i.e. severe bleeding, recurrence and death). Patients with advanced cancer under palliative care (PC) and with VTE, were reviewed during the three years before the study. 71 Patients were diagnosed with VTE. 88.7% were outpatients. The risk factors present were: immobilizations in 28 patients (39.4%), recent surgery in 5 (7%) and previous VTE in 23 (32.5%). Prophylaxis was used in 4 (14.3%) patients with immobilization, no patient with recent surgery, and 10 (43.4%) patients with previous VTE. After diagnosis, all patients received treatment with LMWH in therapeutic dosage. The complications observed were: 6 recurrences (8.5%), 11 VTE-related deaths (15.5%), and bleeding events occured in 8 cases (11.3%), 4 (5.6%) of whom suffered severe bleeding; of these patients, 3 (4.2%) died as a result of the bleeding events. In PC patients with advanced cancer, VTE is a serious complication that conditions control of symptoms. The presence of other risk factors, immobilization and previous VTE, is common and LMWH prophylaxis is limited in clinical practice. The risks vs benefits of anticoagulation need to be counterbalanced.     

Utilisation des modulateurs de la voie de la thrombine et de la protéine C dans les CIVD : résultats des essais cliniques

A correlation between acquired antithrombin (AT) and protein C (PC) deficiencies, multiple organ dysfunction and mortality has been demonstrated in various clinical conditions. In addition, the evolution of these deficiencies over time seems to have a more pronounced predictive value. Thrombin and PC pathways modulation in DIC has been evaluated in various clinical trials. This chapter aims at reviewing the clinical situations associated with DIC and in which the effects of these therapies have been evaluated. Congenital PC deficiency and heparin resistance are not considered here. AT and PC therapies are reviewed with regard to their influence on DIC, multiple organ dysfunction and mortality. AT supplementation improves DIC biomarkers and in some situations, organ dysfunction scores. Its effect on mortality remains to be demonstrated. PC concentrates seem to favourably improve coagulation disorders observed in DIC. However, no controlled study has evaluated its effect on mortality. Activated protein C has been demonstrated to improve survival in patients with severe sepsis at increased risk of death and DIC biomarkers but is associated with an increased risk of bleeding. Finally, heparin improves coagulation parameters observed in DIC but has not been demonstrated to improve survival. Its influence on the effects of other DIC therapies has to be evaluated.     

Thrombophilia in the young

Venous thromboembolism (VTE) is a rare disease that is being increasingly diagnosed and recognized in paediatrics in the past decade, usually as a secondary complication of primary severe underlying diseases. Apart from acquired thrombophilic risk factors, such as lupus anticoagulants, inherited thrombophilias (IT) have been established as risk factors for venous thromboembolic events in adults. In children with idiopathic VTE and in paediatric populations in which thromboses were associated with underlying medical diseases, IT have been described as additional prothrombotic risk factors. Follow-up data for VTE recurrence in children are available and suggest a recurrence rate of approximately 3% in neonates and 8% in other children. Here we present a review of the impact of IT on early onset of VTE and recurrence in children. Statistically significant associations between the IT traits investigated, e.g. factor V G1691A, factor II G20210A, protein C-, protein S-, antithrombin deficiency, elevated lipoprotein (a), combined IT and VTE onset were reported. In addition, statistically significant associations with recurrent VTE were calculated for protein S-, antithrombin-deficiency, and the factor II variant and combined IT. The absolute risk increase for VTE recurrence associated with IT ranged from 9.8 % for children carrying the factorII variant to 26% and 29% in children with combined IT and protein S-deficiency, respectively. Data obtained gave evidence that the detection of IT is clinically meaningful in children with VTE and underlines the importance of a paediatric thrombophilia screening program. Based on these data treatment algorithms have to be discussed.     

Cancer-associated thrombosis in Asia

Thrombosis is a common complication in cancer patients. Although the major inherited risk factors for thrombophilia are different between Asians and Caucasians, the main acquired risk factors that are associated with the development of venous thromboembolism (VTE) in Asians appear to be similar to those for Caucasians. Malignancy is the most important acquired risk factor for VTE in Asians. Recent studies have shown that the incidence of VTE is significant in Asian patients with cancer, particularly those in an advanced stage. Cancer associated VTE is more severe and associated with higher morbidity and mortality. Unprovoked VTE is associated with an increased risk of subsequent cancer diagnosis. A number of international and national guidelines are available to provide guidance to healthcare providers to treat and prevent this serious complication based on best-available evidence. Identifying cancer patients at risk for VTE and use of appropriate thromboprophylaxis in these patients can potentially improve morbidity and mortality. Although direct oral anticoagulants (DOACs) may become an attractive treatment for cancer-associated VTE, further clinical trials are needed to evaluate the safety and efficacy of DOACs directly against LMWH in cancer patients.