D-dimer, factor VIII coagulant activity, low-intensity warfarin and the risk of recurrent venous thromboembolism

BACKGROUND: Elevated plasma D-dimer and factor VIII coagulant activity (FVIIIc) may be associated with the risk of recurrent venous thromboembolism (VTE). OBJECTIVES: To evaluate D-dimer and FVIIIc as risk factors for recurrent VTE and assess the efficacy of extended low-intensity warfarin (target International Normalized Ratio 1.5-2.0) in preventing recurrence by biomarker level. PATIENTS AND METHODS: In the Prevention of Recurrent Venous Thromboembolism trial, 508 idiopathic VTE patients treated for > or = 3 months with full-intensity warfarin, and who had stopped warfarin for 7 weeks on average, were randomized to low-intensity warfarin or placebo and followed for 2.1 years for recurrent VTE. Prerandomization blood samples were analysed for D-dimer and FVIIIc. RESULTS: One-third of participants had elevated baseline D-dimer (> or = 500 ng mL(-1)) and one-fourth, elevated FVIIIc (> or = 150 IU dL(-1)). Adjusting for other risk factors, the hazard ratios (HRs) for recurrent VTE with elevated D-dimer or FVIIIc were 2.0 [95% confidence interval (CI) 1.2-3.4] and 1.5 (95% CI 0.8-2.8), respectively. The association of elevated D-dimer with recurrence was larger among patients with one prior VTE (HR 3.2, 95% CI 1.3-8.0) than in patients with more than one event (HR 1.4, 95% CI 0.7-2.2). For patients with one prior VTE on placebo, the annual recurrence incidence was 10.9% with elevated D-dimer and 2.9% with normal values. Low-intensity warfarin was equally effective in recurrence risk reduction in those with normal or elevated biomarkers. CONCLUSIONS: Among patients with idiopathic VTE, measurement of D-dimer, but not FVIIIc, might be useful for risk stratification. The efficacy of extended low-intensity warfarin therapy did not vary by biomarker level.     

Risk factors for venous thrombosis in medical inpatients: validation of a thrombosis risk score.

BACKGROUND/OBJECTIVES: The occurrence of and risk factors for venous thrombosis (VT) complicating hospital admission in unselected medical inpatients have not been widely studied. PATIENTS and METHODS: In a 400-bed teaching hospital we identified all cases of VT complicating hospital admission between September 2000 and September 2002 using discharge codes and chart review. Controls were randomly selected adult inpatients frequency matched to cases for medical service. RESULTS: The incidence of VT complicating hospital admission was 7.6 per 1000 admissions. On average, VT was diagnosed on the fifth hospital day. The median age of the 65 cases and 123 controls was 68 years and 45% were men. Cases had a 4-fold higher death rate than controls [95% confidence interval (CI) 1.9, 8.8]. At admission, trauma within 3 months, leg edema, pneumonia, platelet count > 350 x 10(3) mm(-3) and certain cancers were associated with risk of VT. Age, body mass index, and acute myocardial infarction were not associated with VT risk. One of three published VT risk models was able to risk stratify patients and was associated with a 2.6-fold increased risk of VT (95% CI 1.3, 5.5). Use of VT prophylaxis did not differ in cases and controls; prophylaxis was used < 1/3 of hospital days in 52% of patients. CONCLUSIONS: VT was common among medical inpatients. Of the risk factors identified, elevated platelet count has not been previously reported. Only one of three published risk scores was associated with risk of inpatient VT. Future study should improve upon risk prediction models for in-hospital VT among medical patients.     

Subclinical atherosclerosis and the risk of future venous thrombosis in the Cardiovascular Health Study

BACKGROUND: Recent reports have suggested an association of atherosclerosis with risk of venous thrombosis. OBJECTIVE: To confirm whether subclinical atherosclerosis is a risk factor for venous thrombosis (VT) among men and women age 65 and older. METHODS: Participants of the Cardiovascular Health Study (n = 4,108) without baseline clinical cardiovascular disease, anticoagulant use or previous VT were followed for a median of 11.7 years after non-invasive assessment of subclinical atherosclerosis using carotid ultrasound (intima-media thickness and presence of plaques), ankle-brachial blood pressure index and electrocardiogram. Each event was classified as idiopathic or secondary. We used Cox proportional hazards regression to estimate the relative risk of overall and idiopathic VT for individuals with and without baseline subclinical atherosclerosis. RESULTS: There were 133 first time VT events. No subclinical atherosclerosis measures were associated with increased risk of overall or idiopathic VT. The adjusted relative risks of overall and idiopathic VT for presence of any type of subclinical disease were 0.60 (95% confidence interval 0.39-0.91) and 0.32 (0.18-0.59), respectively. Most of this association was explained by an inverse association of high-risk carotid plaques (prevalent in 54% of those at risk) with VT. CONCLUSION: Non-invasively measured subclinical atherosclerosis was not associated with increased risk of overall or idiopathic VT in this observational study. Carotid plaques and arterial events during follow up were inversely associated, a finding that requires further study.     

Factor VII coagulant activity, factor VII −670A/C and −402G/A polymorphisms, and risk of venous thromboembolism

BACKGROUND: Most epidemiological studies have found no association between levels of factor (F) VII:C and venous thromboembolism (VTE). Our Longitudinal Investigation of Thromboembolism Etiology (LITE) had, in contrast, reported an independent, increased risk of VTE after 7.8 years of follow-up for those with high baseline levels of FVII:C. OBJECTIVE: To confirm whether FVII:C is associated with VTE after 12.6 years of follow-up and to examine whether two FVII gene polymorphisms (-670A/C and -402G/A) are related to VTE occurrence. METHODS: In 19 091 LITE participants with no prior history of VTE or cancer, we measured FVII:C at baseline and identified 404 new VTEs. We also performed a nested case-control study to relate the polymorphisms to VTE (n = 490 without exclusion for cancer or prior VTE). RESULTS: FVII:C was not independently associated with VTE occurrence after extended follow-up. Multivariable-adjusted rate ratios for VTE were 1.00, 1.00, 0.94, 1.00, and 1.38 (P-trend = 0.48) for the <25th, 25th-49th, 50th-74th, 75th-94th, and >or=95th percentiles of FVII:C, respectively. The -670C and -402A alleles were in high linkage disequilibrium, and both were associated with greater FVII:C levels. However, neither polymorphism was associated with VTE occurrence. CONCLUSION: After extended follow-up, LITE offers little evidence that a greater FVII level is a risk factor for VTE.     

Unprovoked recurrent venous thrombosis: prediction by D-dimer and clinical risk factors

Summary.  Background:  The aim of the study was to determine the predictive value of D-dimer measurement for unprovoked recurrent venous thrombosis and the influence of sex, age and type of first event (unprovoked or provoked). Methods:  Prospective cohort study of 272 patients with a first episode of venous thrombosis that was unprovoked or provoked by a non-surgical trigger. Findings:  The cumulative rate of unprovoked recurrence in patients with a positive D-dimer was 20% at 5 years [5.5/100 patient-years, 95% confidence interval (CI) 3.7–7.8] and in patients with a negative D-dimer 17% (4.1/100 patient-years, 95% CI 2.3–6.9). The rates are not different (hazard ratio 1.3, 95% CI 0.7–2.5). After adjustment for clinical risk factors a positive D-dimer result was significantly associated with an increased risk of unprovoked recurrent thrombosis (hazard ratio 2.0, 95% CI 1.01–3.9). The strongest indicator of risk of recurrence was male sex (hazard ratio 3.3 unadjusted and 2.9 after adjustment). The only determinant of D-dimer in a linear regression model was age ( P  <   0.001). Conclusions:  The analysis indicates that clinical risk factors confound the association between D-dimer and risk of recurrence and when adjusted for these confounders a positive D-dimer result is significantly associated with unprovoked recurrence. The clinical utility of D-dimer measurement in individual patients should be interpreted in conjunction with clinical risk factors.     

Reactive thrombocytosis and risk of subsequent venous thromboembolism: a cohort study

Summary. Background: It is uncertain whether reactive thrombocytosis is associated with an increased risk of venous thromboembolism. This study assessed the incidence of reactive thrombocytosis, defined as platelet count ≥ 500 × 10⁹ L^?1, at intensive care unit discharge and its association with subsequent venous thromboembolism. Methods and Results: This cohort study involved linkage of routinely collected intensive care unit, laboratory, radiology and death registry data of critically ill patients admitted to the intensive care unit between January 2009 and March 2010. The census date for survival and radiologically confirmed venous thromboembolism was 31 October 2011. Of the 1446 patients who survived to intensive care unit discharge, 139 patients had reactive thrombocytosis (9.6%, 95% confidence interval [CI] 8.2–11.2%). Twenty‐nine patients developed venous thromboembolism after discharge (2%, 95% CI 1.4–2.9%; 67 per 100 person‐years, 95% CI 45–97) and the median time to develop venous thromboembolism was 25 days (interquartile range 8–148). Reactive thrombocytosis was associated with an increased risk of subsequent venous thromboembolism (hazard ratio 5.3, 95% CI 1.7–16.4), after adjusting for other covariates. Platelet counts explained about 34% of the variability in the risk of venous thromboembolism and had a relatively linear relationship with the risk of venous thromboembolism when the platelet counts were > 400 × 10⁹ L^?1. Venous thromboembolism after intensive care unit discharge was associated with an increased risk of mortality (hazard ratio 2.0, 95% CI 1.1–3.9), after adjusting for reactive thrombocytosis. Conclusions: Reactive thrombocytosis during the recovery phase of critical illness was associated with an increased risk of subsequent venous thromboembolism.     

Venous thromboembolism and atherosclerosis: is there a link?

Summary.  After the initial demonstration provided 4 years ago by a case–control study in the New England Journal of Medicine , numerous investigations have addressed the association between venous and arterial thrombotic disorders. According to the results of recent studies, the two conditions are likely to share common risk factors, including age, obesity, cigarette smoking, diabetes mellitus, arterial hypertension, hyperlipemia and metabolic syndrome. The nature of this association is unclear. On the one hand, atherosclerosis has the potential to promote the development of thrombotic disorders in the venous system. On the other hand, the two clinical conditions can be simultaneously triggered by biological stimuli responsible for activating coagulation and inflammatory pathways in both the arterial and the venous system. Based on the results of two population-based studies carried out in the USA, atherosclerosis is unlikely to constitute a risk factor for venous thromboembolic (VTE) disorders. Several recent studies have consistently shown that subjects with VTE of unknown origin are at a higher risk of subsequent arterial cardiovascular events than subjects with secondary VTE and matched control individuals. In conclusion, the separate nature of arterial and venous disorders has been challenged. Future studies are needed to clarify the nature of this association, to assess its extent, and to evaluate its implications for clinical practice.     

Association between migraine and risk of venous thromboembolism: A nationwide cohort study

Background .—The link between arterial thromboembolism and migraine is well‐documented; however, few studies investigated the link between venous thromboembolism (VTE) and migraine. We aimed to evaluate the association between migraine and VTE and to examine whether demographics or comorbid risk factors modulate VTE development. Methods. —We conducted a cohort study accessing a nationwide claims‐based database with an adult cohort of 102,159 neurologist‐diagnosed migraine patients, and 102,159 nonheadache comparison subjects, matched on sex and propensity score for the diagnosis of migraine. Both cohorts were followed until the end of 2010, death, or VTE development. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated based on Cox proportional hazards regression analyses and compared between the two groups. Results .—During a mean follow‐up period of 4.2 years, VTE developed in 226 patients (460,047 person‐years) in the migraine cohort and in 203 subjects (462,401 person‐years) in the comparison cohort. Overall, likelihood of VTE for the migraine cohort did not differ from that in the comparison cohort (aHR 1.12; 95% CI, 0.92–1.35; P = .251). However, subgroup analysis by migraine subtypes (P = .004 for interaction) revealed an elevated risk of VTE in patients with migraine with aura (aHR 2.42; 95% CI, 1.40–4.19; P = .002), but not in those with migraine without aura. The association was not altered in subsequent subgroup analyses and sensitivity analyses. Conclusions Risk of VTE development is elevated specifically in patients diagnosed with migraine with aura. This association suggests a linked disease mechanism and warrants further exploration.     

A prospective study of anticardiolipin antibodies as a risk factor for venous thrombosis in a general population (the HUNT study)

Summary. We prospectively examined whether there is an association between elevated anticardiolipin antibody levels and the risk for a future first venous thrombosis (VT) in a general population. We studied this in a large population‐based nested case‐cohort study of 508 VT cases and 1464 matched control subjects from a cohort of 66 140 participants in the Health Study of Nord‐Trøndelag in Norway. Venous thrombosis was validated using standardized criteria for venous thrombosis and pulmonary embolism. Prethrombotic serum anticardiolipin antibodies were measured by an enzyme‐linked immunoassay. There was no association between elevated anticardiolipin antibody levels and subsequent venous thrombosis, overall or after stratification by sex, different age groups or idiopathic vs. secondary thrombosis. The overall odds ratio was 1.11 (95% CI: 0.71–1.74) for greater than vs. less than the 95th percentile of anticardiolipin antibody levels. In conclusion, in this general population sample elevated anticardiolipin antibody levels was not a risk factor for subsequent venous thrombosis.     

Genetic variation within the anticoagulant,procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism

Summary. Background: Venous thromboembolism (VTE) is highly heritable (estimated heritability [h²] = 0.62) and likely to be a result of multigenic action. Objective: To systematically test variation within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways for an independent association with VTE. Methods: Non‐Hispanic adults of European ancestry with objectively‐diagnosed VTE, and age‐ and sex‐ matched controls, were genotyped for 13 031 single nucleotide polymorphisms (SNPs) within 764 genes. Analyses (n = 12 296 SNPs) were performed with plink using an additive genetic model and adjusted for age, sex, state of residence, and myocardial infarction or stroke. Results: Among 2927 individuals, one or more SNPs within ABO, F2, F5, F11, KLKB1, SELP and SCUBE1 were significantly associated with VTE, including factor (F) V Leiden, prothrombin G20210A, ABO non‐O blood type, and a novel association with ABO rs2519093 (OR = 1.68, P‐value = 8.08 × 10^?16) that was independent of blood type. In stratified analyses, SNPs in the following genes were significantly associated with VTE: F5 and ABO among both genders and LY86 among women; F2, ABO and KLKB1 among FV Leiden non‐carriers; F5, F11, KLKB1 and GFRA1 in those with ABO non‐O blood type; and ABO, F5, F11, KLKB1, SCUBE1 and SELP among prothrombin G20210A non‐carriers. The ABO rs2519093 population‐attributable risk (PAR) exceeded that of FV Leiden and prothrombin G20210A, and the joint PAR of FV Leiden, prothrombin G20210A, ABO non‐O and ABO rs2519093 was 0.40. Conclusions: Anticoagulant, procoagulant, fibrinolytic and innate immunity pathway genetic variation accounts for a large proportion of VTE among non‐Hispanic adults of European ancestry.     

Psychosocial factors and venous thromboembolism: a long-term follow-up study of Swedish men

Summary.  Background:  The link between psychosocial factors and coronary heart disease is well established, but although effects on coagulation and fibrinolysis variables may be implicated, no population-based study has sought to determine whether venous thromboembolism is similarly related to psychosocial factors. Objective:  To determine whether venous thromboembolism (deep vein thrombosis or pulmonary embolism) is related to psychosocial factors. Patients/methods:   A stress questionnaire was filled in by 6958 men at baseline from 1970 to 1973, participants in a cardiovascular intervention trial. Their occupation was used to determine socio-economic status. Results:  After a maximum follow-up of 28.8 years, 358 cases of deep vein thrombosis and/or pulmonary embolism were identified through the Swedish hospital discharge and cause-specific death registries. In comparison with men who, at baseline, had no or moderate stress, men with persistent stress had increased risk of pulmonary embolism [hazard ratio (HR)=1.80, 95% CI: 1.21–2.67]. After multivariable adjustment, the HR decreased slightly to 1.66 (95% CI: 1.12–2.48). When compared with manual workers, men with white-collar jobs at intermediate or high level and professionals showed an inverse relationship between occupational class and pulmonary embolism (multiple-adjusted HR=0.57, 95% CI: 0.39–0.83). Deep vein thrombosis was not significantly related to either stress or occupational class. Conclusion:  Both persistent stress and low occupational class were independently related to future pulmonary embolism. The mechanisms are unknown, but effects on coagulation and fibrinolytic factors are likely.     

Smoking and venous thromboembolism: a Danish follow-up study

Summary.  Background:  Large-scale prospective studies are needed to assess whether smoking is associated with venous thromboembolism (VTE) (i.e. deep venous thrombosis and pulmonary embolism) independently of established risk factors. Objective:  To investigate the association between smoking and the risk of VTE among middle-aged men and women. Methods:  From 1993 to 1997, 27 178 men and 29 875 women, aged 50–64 years and born in Denmark, were recruited into the Danish prospective study 'Diet, Cancer and Health'. During follow-up, VTE cases were identified in the Danish National Patient Registry. Medical records were reviewed and only verified VTE cases were included in the study. Baseline data on smoking and potential confounders were included in gender stratified Cox proportional hazard models to asses the association between smoking and the risk of VTE. The analyses were adjusted for alcohol intake, body mass index, physical activity, and in women also for use of hormone replacement therapy. Results:  During follow-up, 641 incident cases of VTE were verified. We found a positive association between current smoking and VTE, with a hazard ratio of 1.52 (95% CI, 1.15–2.00) for smoking women and 1.32 (95% CI, 1.00–1.74) for smoking men, and a positive dose-response relationship. Former smokers had the same hazard as never smokers. Conclusions:  Smoking was an independent risk factor for VTE among middle-aged men and women. Former smokers have the same risk of VTE as never smokers, indicating acute effects of smoking, and underscoring the potential benefits of smoking cessation.     

Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study

Summary. Background: Current use of menopausal hormone therapy (HT) increases the risk of venous thromboembolism (VTE) and the formulations used may affect risk. Methods: A total of 1 058 259 postmenopausal UK women were followed by record linkage to routinely collected National Health Service hospital admission and death records. HT use and risk of VTE was examined using Cox regression to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: During 3.3 million years of follow‐up, 2200 women had an incident VTE, diagnosed, on average, 1.5 years after last reporting HT use. RRs in current vs. never users at last reporting varied by HT formulation: the risk was significantly greater for oral estrogen‐progestin than oral estrogen‐only therapy (RR = 2.07 [95%CI, 1.86–2.31] vs. 1.42 [1.21–1.66]), with no increased risk with transdermal estrogen‐only therapy (0.82 [0.64–1.06]). Among users of oral estrogen‐progestin, the risk from HT varied by progestin type, with significantly greater risks for preparations containing medroxyprogesterone acetate than other progestins (2.67 [2.25–3.17] vs. 1.91 [1.69–2.17]; P_{heterogeneity} = 0.0007). Current users of oral HT at last reporting had twice the risk of VTE in the first 2 years after starting HT than later (P_{heterogeneity} = 0.0006). Associations were similar for deep vein thrombosis with and without pulmonary embolism. Over 5 years, 1 in 660 who had never used HT were admitted to hospital for (or died from) pulmonary embolism, compared with 1 in 475 current users of oral estrogen‐only HT,1 in 390 users of estrogen‐progestin HT containing norethisterone/norgestrel, and 1 in 250 users of estrogen‐progestin HT containing medroxyprogesterone acetate. Conclusions: The risk of VTE varied considerably by HT formulation, being greatest in users of oral estrogen‐progestin HT, especially formulations containing medroxyprogesterone acetate.     

The metabolic syndrome and the risk of venous thrombosis: a case–control study

OBJECTIVE: The results of recent studies have suggested that patients with idiopathic venous thromboembolism (VTE) might be at increased risk of asymptomatic atherosclerosis and cardiovascular events. The metabolic syndrome is a cluster of risk factors for atherosclerosis. Its impact on VTE is unknown. METHODS: In a case-control study, consecutive patients with objectively confirmed deep vein thrombosis (DVT) and control subjects with objectively excluded DVT underwent clinical assessment for the presence of the metabolic syndrome according to the National Cholesterol Education Program criteria. The presence of known risk factors for DVT was documented. Patients with DVT secondary to cancer were excluded. The prevalence of the metabolic syndrome was compared between patients with idiopathic DVT and controls. RESULTS: We enrolled 93 patients with a first episode of idiopathic DVT and 107 controls. The mean age was 65.1 and 63.7 years, respectively. The metabolic syndrome was diagnosed in 50.5% of patients with idiopathic DVT and in 34.6% of controls [odds ratio (OR) 1.93; 95% confidence interval (CI) 1.05, 3.56]. After adjustment for age, sex, body mass index, and smoke, the metabolic syndrome remained independently associated with idiopathic DVT (OR 1.94; 95% CI 1.04, 3.63). In patients with secondary DVT, the prevalence of the metabolic syndrome was 27%. CONCLUSIONS: The metabolic syndrome may play a role in the pathogenesis of idiopathic DVT and may act as link between venous thrombosis and atherosclerosis.     

内科住院患者静脉血栓栓塞症的预防

现已明确,对有静脉血栓栓塞症（VTE）高危风险的内科住院患者给予血栓预防措施可明确降低VTE的发病率和病死率。2009年我国颁布了＂内科住院患者静脉血栓栓塞症预防的中国专家建议＂〔1〕。2012年美国胸科医师学会颁布了血栓形成抗栓治疗和预防第9版指南〔2〕,此文对该指南中有关内科住院患者VTE预防的建议进行解读。