Risk factors for venous thrombosis – current understanding from an epidemiological point of view

Epidemiological research throughout the last 50 years has provided the long list of risk factors for venous thrombosis that are known today. Although this has advanced our current understanding about the aetiology of thrombosis, it does not give us all the answers: many people have several of these risk factors but never develop thrombosis; others suffer from thrombosis but have none. In this review, we discuss how risk factors for venous thrombosis can be interpreted with use of several epidemiological models. We comment on how to explain why risk factors for first venous thrombosis differ from recurrent venous thrombosis, and use a causal model to better understand risk of first and recurrent venous thrombosis.     

Prevalence of hereditary thrombophilia in patients with thrombosis in different venous systems

The prevalence of hereditary thrombophilia is well known in patients with lower-extremity thrombosis but only poorly studied in patients with thrombosis at unusual sites. Consequently, it is still unclear whether such patients should generally be screened for hereditary thrombophilia. We retrospectively analyzed 260 patients with thrombosis at unusual sites including thrombosis in portal, cerebral, retinal, and upper-extremity veins with respect to the prevalence of FV Leiden, prothrombin G20210A, protein C, protein S, and antithrombin deficiency. In addition, all thrombotic episodes were analyzed for circumstantial risk factors. Used as controls, healthy volunteers (120) and patients with lower-extremity thrombosis (292) showed overall prevalence of hereditary thrombophilia of 9.1% and 39.0%, respectively. The corresponding numbers were 33.3%, 34.3%, and 39.0% in patients with portal vein, upper-extremity, and lower-extremity thrombosis, respectively. In patients with cerebral vein thrombosis, however, the prevalence was significantly lower (23.5%). Patients with retinal vein occlusion did not show an increased frequency of thrombophilia at all (5.9%). In all five groups FV Leiden was by far the most frequent defect (4.4-27.1%), while prothrombin G20210A occurred rarer (2.5-7.6%). Protein C, protein S, and antithrombin deficiency were much less prevalent (0-3.1%) except for patients with portal vein thrombosis (4.8-7.1%). Compared to healthy individuals, the relative risk of thrombosis was 4.3 (2.2-8.1), 3.8 (1.8-7.7), 2.5 (1.0-6.1), 3.7 (1.5-8.6), and 0.6 (0.2-2.1) for patients with lower-extremity, upper-extremity, cerebral vein, portal vein, and retinal vein thrombosis, respectively. Circumstantial risk factors were more frequent in patients without than with hereditary thrombophilia and were found most often in patients with upper-extremity thrombosis. In each group the most frequent circumstantial risk factor was different. However, oral contraceptives and cancer were found in all five groups. In conclusion, independent upon the presence of circumstantial risk factors, screening for hereditary thrombophilia is warranted in all patients with thrombosis at unusual sites except in those with retinal vein occlusion.     

Direct oral anticoagulant use in patients with thrombophilia,antiphospholipid syndrome or venous thrombosis of unusual sites: A narrative review

Direct oral anticoagulants (DOACs) are indicated in the treatment and prevention of venous thromboembolism (VTE). However, the use of DOACs in unusual VTE, including cerebral venous thrombosis (CVT) and splanchnic venous thrombosis (SVT), and in patients with biological thrombophilia including minor thrombophilia (Factor V Leiden and prothrombin G20210A), major innate thrombophilia (protein C and S deficiency, and antithrombin) and major acquired thrombophilia (antiphospholipid syndrome [APS]), remains controversial due to the paucity of available data. There are some reports of DOACs use in the initial treatment or long-term maintenance of patients with either CVT or SVT, but their efficacy remains unclear. The efficacy of DOACs may be suitable in patients with biological minor or major thrombophilia. The use of DOACs for the long-term maintenance of patients with APS is more contentious. Randomized clinical trials, which are currently underway, should offer definitive insight into the efficacy and safety profiles of DOACs in these patient populations.     

Thrombophilic risk factors among 16 Lebanese patients with cerebral venous and sinus thrombosis

Cerebral venous and sinus thrombosis (CVST) is a multifaceted disorder. The frequency of inherited and acquired thrombophilia among 16 CVST patients was evaluated. The mean age of the patients was 22.9 years. Five out of the 16 CVST patients (31.2%) showed the G1691A mutation of factor V. The frequency of the C677T methylenetetrahydrofolate reductase (MTHFR) genotype was 50% (8/16) in patients (2 of them were homozygous). Four of the patients (25%) had both factor V Leiden and MTHFR mutation. Three of the patients had positive antiphospholipid antibodies. At the time of CVST, 2 female patients were taking oral contraceptive pills. Four patients were known to have malignancies. Despite the limitation of the sample size, we identified an inherited coagulopathy at high rate in our patients. Combined inherited thrombophilia was also present in 25% of patients. This finding supports the impression of a multifactorial process leading to CVST in Lebanese patients.     

Advances in understanding the molecular mechanisms that maintain normal haemostasis

Blood clot formation to stem bleeding from an injured blood vessel arises from a complex series of cellular and biochemical events, which, when dysregulated, predispose to an increased risk of thrombosis or bleeding. Similarly, haemostatic regulation of clot growth and size is exquisitely controlled by a series of anticoagulant ‘checkpoints', that exert their inhibitory activity at distinct stages in the steps leading to clot formation. Although the major plasma protein constituents required for haemostasis have now been largely elucidated and the molecular events that lead to clot formation are well understood, defining a fuller appreciation of the importance, location and regulation of each haemostatic process remains a fertile area of ongoing research. In this review article, we first provide an overview of the original ‘waterfall' or ‘cascade' hypothesis of blood coagulation as it was defined in the 1960s. We subsequently discuss how this original model has been refined over time to incorporate accumulating data that has enabled a more nuanced consideration of the role of specific proteins, receptors and lipids in dictating the spatial and temporal development of a blood clot.     

Pseudohomozygosity for activated protein C resistance is a risk factor for venous thrombosis

Pseudohomozygosity for activated protein C resistance (APC-r) is a rare condition due to the association of heterozygous FV Leiden mutation and partial type I FV deficiency. To assess the risk of venous thromboembolism in these subjects, seven families including 11 pseudohomozygotes and 45 relatives were examined. Among the relatives, 16 were heterozygous FV Leiden carriers, nine showed partial FV deficiency and 20 no abnormalities. Deep vein thrombosis occurred in 4/11 (36.3%) pseudohomozygous patients versus 6/16 (37. 4%) FV Leiden carriers and 1/20 (5%) normal relatives. Pseudohomozygotes and FV Leiden carriers had a significantly increased risk of venous thrombosis in comparison to normal relatives (RR 8.8 and 5.7, respectively). There was no difference between the thrombotic risk of pseudohomozygous subjects and of FV Leiden carriers (RR 1.6, 95% CI 0.43-5.7). Furthermore, there was no difference in thrombosis-free survival between pseudohomozygotes and 45 consecutive FV Leiden heterozygous outpatients, suggesting that a referral bias may explain the apparent younger age of thrombosis in the pseudohomozygotes in comparison to relatives with FV Leiden heterozygosity (27 years v 54 years; P = 0.01). Pseudohomozygosity for APC resistance carries a significantly higher risk for venous thromboembolism in comparison to normal subjects, but probably not in comparison to heterozygous FV Leiden carriers.     

深静脉血栓患者并发肺栓塞危险因素荟萃分析

目的 通过荟萃分析探讨深静脉血栓（DVT）患者并发肺栓塞（PE）的危险因素。方法 计算机检索Pubmed、Embase、Cochrane Library、web of science、中国知网、万方数据知识服务中心、维普期刊资源整合服务平台、中国生物医学文献数据库(CBM)已发表的关于DVT患者并发PE相关危险因素的病例对照研究,检索时限为建库以来至2020年4月15日,两名研究者按照Cochrane系统评价方法及本文纳入和排除标准筛选文献、提取资料并评价质量后,采用Revman5.3软件进行荟萃分析。结果 共纳入15篇病例对照研究,荟萃分析结果显示,右下肢DVT（OR=2.09,95%CI [1.60～2.73]）、双下肢DVT（OR=1.96 95%CI [1.27～3.03]）、近端DVT（OR=1.95 95%CI [1.56～2.43]）、VTE史（OR=1.93 95%CI [1.46～2.54]）、无明显诱因VTE（OR=2.42 95%CI [1.64～3.59]）、外科手术史（OR=2.86 95%CI [2.02～4.04]）、恶性肿瘤（OR=2.50 95%CI [1.63～3.83]）、心脏疾病（OR=3.22 95%CI [1.85～5.59]）、冠心病（OR=6.12,95%CI[1.04～36.11]）、心脏瓣膜病（OR=5.66 95%CI[1.79～17.87]）、慢性肺部疾病（OR=1.59 95%CI [1.39～1.81]）、呼吸道感染（OR=2.07 95%CI [1.29～3.31]）、糖尿病（OR=3.52 95%CI [1.86～6.67]）、高C反应蛋白（CRP）（OR=1.04 95%CI [1.02～1.04]）合并效应量后差异有统计学意义,简单描述性分析结果显示高D-二聚体是DVT患者并发PE的危险因素,年龄与DVT患者并发PE风险的相关性尚不明确。结论 右下肢DVT、双下肢DVT、近端DVT、VTE史、无明显诱因VTE、外科手术史、恶性肿瘤、心脏疾病、冠心病、心脏瓣膜病、慢性肺部疾病、呼吸道感染、糖尿病、高D-二聚体、高CRP是DVT患者并发PE相关危险因素,年龄与DVT患者并发PE风险的相关性尚不明确。     

Difference in absolute risk of venous and arterial thrombosis between familial protein S deficiency type I and type III. Results from a family cohort study to assess the clinical impact of a laboratory test-based classification

Hereditary protein S (PS) deficiency type I is an established risk factor for venous thromboembolism. Contradictionary data on type III deficiency suggests a difference in risk between both types. We studied 156 first degree relatives (90% of eligible relatives) from type I deficient probands (cohort 1) and 268 (88%) from type III deficient probands (cohort 2) to determine the absolute risk of venous and arterial thromboembolism. Annual incidences of venous thromboembolism were 1.47 and 0.17 per 100 person-years in deficient and non-deficient relatives in cohort 1 [relative risk (RR) 8.9; 95% confidence interval (CI) 2.6-30.0], and 0.27 vs. 0.24 in cohort 2 (RR 0.9; 95% CI 0.4-2.2). Type III deficiency was demonstrated in 20% of non-deficient relatives in cohort 1 and the annual incidence in this subgroup was 0.70 (RR 4.3;0.95-19.0). The cut-off level of free PS to identify subjects at risk was 30%, the lower limit of its normal range (65%). PS deficiency was not a risk factor for arterial thromboembolism. In conclusion, type I deficiency was found to be a strong risk factor for venous thromboembolism, in contrast with type III deficiency. This was because of lower free PS levels in type I deficient subjects and a free PS cut-off level far below the lower limit of its normal range.     

Clinical features of venous insufficiency and the risk of venous thrombosis in older people

Venous thrombosis is common in older age, with an incidence of 0·5–1% per year in those aged >70 years. Stasis of blood flow is an important contributor to the development of thrombosis and may be due to venous insufficiency in the legs. The risk of thrombosis associated with clinical features of venous insufficiency, i.e., varicose veins, leg ulcers and leg oedema, obtained with a standardized interview was assessed in the Age and Thrombosis Acquired and Genetic risk factors in the Elderly (AT‐AGE) study. The AT‐AGE study is a case–control study in individuals aged 70 years and older (401 cases with a first‐time venous thrombosis and 431 control subjects). We calculated odds ratios (ORs) and corresponding 95% confidence intervals (CI) adjusted for age, sex and study centre. Varicose veins and leg ulcer were associated with a 1·6‐fold (95% CI 1·2–2·3) and 3·3‐fold increased risk of thrombosis (95% CI 1·6–6·7), respectively, while the risk was increased 3·0‐fold (95% CI 2·1–4·5) in the presence of leg oedema. The risk of thrombosis was highest when all three risk factors occurred simultaneously (OR: 10·5; 95% CI 1·3–86·1). In conclusion, clinical features of venous insufficiency, i.e., varicose veins, leg ulcers and leg oedema, are risk factors for venous thrombosis in older people.     

原发病对老年全髋关节置换术后下肢深静脉血栓形成的影响

目的 探讨不同原发病对老年全髋关节置换术后下肢深静脉血栓形成（deep venous thrombosis,DVT）的影响.方法 147例单侧全髋关节置换术病人,根据原发病不同分为两组：骨折组68例,均为股骨颈骨折患者,骨病组79例.术前常规检查血浆部分凝血活酶时间（APTT）、凝血酶原时间（PT）、凝血酶凝固时间（thrombin time,TT）、纤维蛋白原（fibrinogen,Fib）含量;对术后出现患肢肿胀和/或疼痛,下肢伴有或不伴有Homans征/Neuhofs征阳性的患者常规应用加压超声技术进行超声多谱勒检查.结果 骨折组和骨病组的APTT、PT、TT、Fib水平及下肢DVT发生率比较具有显著性差异（P＜0.05）.结论 股骨颈骨折是老年全髋关节置换术后下肢DVT发生的高危因素.     

深静脉血栓患者抗凝与纤溶功能研究

目的 :通过对深静脉血栓形成 (DVT)患者抗凝和纤溶系统各种指标的检测 ,探讨高凝状态在DVT患者发病机制中的重要作用。方法 :选择 72例经超声和 (或 )静脉造影确诊的DVT患者 ,以 70例健康体检者作为对照组测定抗凝血酶 Ⅲ (AT Ⅲ )活性、蛋白C(PC)活性、总蛋白抗原S(PS)、纤溶酶原 (Plg)活性、纤溶酶原激活剂抑制物 1(PAI 1)、D 二聚体 (D dimer)、尿激酶 (uPA)和尿激酶受体 (uPAR)含量。结果 :DVT患者的AT Ⅲ活性、PC活性和PS含量明显低于对照组 ,患者组中抗凝蛋白AT Ⅲ、PC和PS缺陷的发生率明显高于对照组 ,其中复发组的AT Ⅲ、PC和PS缺陷的发生率明显高于初发组。DVT患者的Plg含量明显低于对照组 ,而PAI 1、D dimer、uPA、uPAR水平明显高于对照组。患者组中D dimer含量 >5 0 0ng/L者占97.2 % ,而对照组仅占 1.4 %。结论 :DVT患者中普遍存在抗凝功能的降低 ,表现为各种抗凝蛋白水平的降低 ,DVT患者中抗凝蛋白缺陷的发生率明显高于对照组 ,复发DVT患者的抗凝蛋白缺陷发生率明显高于初发患者 ,证明抗凝蛋白缺陷是DVT发生和复发的重要因素之一。DVT患者普遍存在纤溶功能的降低 ,表现为Plg含量的降低和PAI 1含量的升高 ,患者组uPA和uPAR含量明显高于对照组 ,主要是由于uPA/uPAR介导的纤溶活性在DVT发生后     

Central venous catheter-associated thrombosis in severe haemophilia

Significant subclavian vein thromboses associated with indwelling fully implanted (port-a-cath) devices are described in two boys with severe haemophilia A and factor VIII inhibitors. Investigations were prompted by prominent chest wall veins in one case, whereas the thrombosis was a chance finding in the other case during investigation of mechanical dislocation of the catheter tubing. Extensive collateral venous circulations were demonstrated by venography in both instances indicating that the thrombus had been present for some time. Possible contributing factors to the thromboses included desensitization therapy (both patients), high-dose FEIBA (in one patient) and use of lower doses of heparin for line flush than that recommended by some authors. Neither patient had a familial or non-familial predisposition to thrombosis.     

中心静脉置管与深静脉血栓的关系

目前深静脉置管被广泛应用于临床,主要由于它具有方便、操作简单、减少患者因反复穿刺引起静脉炎,并且拔管后静脉仍可复通等优点,为患者抢救、治疗开通了快速输液通道,并可监测中心静脉压.但是该操作也存在一些潜在的危险,如感染、导管阻塞及血栓形成等并发症,严重栓塞者甚至会危及生命.目前在深静脉血栓形成之前是否需要使用抗凝剂预防、血栓形成后抗凝药的规范使用以及手术时机的选择等方面还没有定论.本文主要针对中心静脉置管相关性血栓的原因、临床表现及防治进行分析,寻找与血栓形成最相关的因素,进而能够更好地预防深静脉血栓的形成.     

深静脉血栓复发危险因素分析

目的探讨深静脉血栓复发的相关的危险因素。方法通过空军总医院病案检索系统纳入2010年1月-2013年1月期间住院治疗并确诊为深静脉血栓形成(DVT)患者170例,采集患者的性别、年龄、合并疾病及复发情况等相关数据,建立数据库。对引起DVT复发可能的危险因素进行赋值,采用二分类Logistic回归分析判断DVT复发危险因素。结果 170例DVT患者中深静脉血栓复发率为52.9%。合并恶性肿瘤患者复发率为67.2%;合并肾病综合征或终末期肾病患者复发率为95.7%;合并1种及1种以上疾病患者复发率为76.5%;使用下腔静脉滤器患者复发率为25.0%;深静脉血管创伤性操作患者复发率为80.5%;骨科手术患者复发率为12.5%;肿瘤手术患者复发率为76.0%。合并肿瘤(OR=11.710,95%CI:2.302~59.553)、肾病综合征或终末期肾病(OR=73.188,95%CI:2.969~1803.904)、合并1种及1种以上疾病(OR=58.338,95%CI:11.519~295.458)是深静脉血栓复发的独立危险因素。结论深静脉血栓形成患者合并肿瘤、肾病综合征或终末期肾病及合并1种或1种以上疾病时要注意深静脉血栓复发的预防。     

Guidelines on travel‐related venous thrombosis

• ? Long duration travel is a weak risk factor for the development of venous thromboembolism (VTE). The incidence of VTE after flights of >4 h is 1 in 4656 and for flights of more than 8 h in low and intermediate risk flyers is around 0·5%.
• ? Severe symptomatic pulmonary embolism in the period immediately after travel is extremely rare after flights of <8 h. In flights over 12 h the rate is 5 per million.
• ? VTE may be attributable to travel if it occurs up to 8 weeks following the journey.
• ? The risk of travel‐related thrombosis is higher in individuals with pre‐existing risk factors for the development of VTE.
• ? There is no evidence for an association between dehydration and travel‐associated VTE and so whilst maintaining good hydration is unlikely to be harmful it cannot be strongly recommended for prevention of thrombosis (recommendation grade 2, level of evidence, B).
• ? There is indirect evidence that maintaining mobility may prevent VTE and, in view of the likely pathogenesis of travel‐related VTE, maintaining mobility is a reasonable precaution for all travellers on journeys over 3 h (2B).
• ? Global use of compression stockings and anticoagulants for long distance travel is not indicated (1C).
• ? Assessment of risk should be made on an individual basis but it is likely that recent major surgery (within 1 month), active malignancy, previous unprovoked VTE, previous travel‐related VTE with no associated temporary risk factor or presence of more than one risk factor identifies those travellers at highest thrombosis risk (1C).
• ? Travellers at the highest risk of travel‐related thrombosis undertaking journeys of >3 h should wear well fitted below knee compression hosiery (2B).
• ? Where pharmacological prophylaxis is considered appropriate, anticoagulants as opposed to anti‐platelet drugs are recommended based on the observation that, in other clinical scenarios, they provide more effective thromboprophylaxis. Usual contraindications to any form of thromboprophylaxis need to be borne in mind (2C).