Risk Of Unprovoked Venous Thromboembolism Research Articles

Association between body mass index, waist circumference, and relative fat mass with the risk of first unprovoked venous thromboembolism

Background and aimsObesity defined by body mass index (BMI) is independently associated with venous thromboembolism (VTE). Abdominal obesity, defined by waist circumference, is a predictor of cardiovascular events. Recently, relative fat mass (RFM) was proposed as a marker of cardiovascular risk. We assessed the role of three different measures of obesity to predict unprovoked VTE in a longitudinal study. Methods and resultsMoli-sani is a prospective cohort study carried out in the general population of the Molise region, Italy. A total of 23,538 individuals (48% men, age 55.4 years) enrolled between 2005 and 2010 were eligible. Patients on anticoagulant treatment were excluded. BMI ≥30 kg/m2 defined obesity, waist circumference >102 cm for men or 88 cm for women defined abdominal obesity, tertiles of RFM were compared. The long-term incidence of first unprovoked VTE during follow-up was assessed. Overall, 29.6% individuals were obese and 44.2% had abdominal obesity. A total of 66 first unprovoked VTE events were diagnosed during a median follow-up of 8.2 years. After multivariable Cox regression analysis, the risk of unprovoked VTE was significantly higher in obese participants (HR 1.89, 95% CI 1.16–3.07) than in participants with BMI <30; in subjects with abdominal obesity than with normal waist circumference (HR 2.19, 1.26–3.81); and in subjects with third vs first RFM tertile index (HR 2.46, 1.15–5.28). The areas under the curves for the models including the three obesity indexes were comparable. ConclusionsThree indexes of obesity based on BMI, waist circumference or RFM similarly predict first occurrence of unprovoked VTE.

Elevated plasma levels of P‐selectin glycoprotein ligand‐1‐positive microvesicles in patients with unprovoked venous thromboembolism

Background Microvesicles (MVs) express antigens from their parental cells and have a highly procoagulant surface. Animal studies suggest that P-selectin glycoprotein ligand-1-positive (PSGL-1+ ) MVs play a role in the pathogenesis of venous thromboembolism (VTE). Objective The aim of this study was to determine plasma levels, the cellular origin and the morphological characteristics of PSGL-1+ MVs in patients with unprovoked VTE. Methods We conducted a population-based case-control study in 20 patients with a history of unprovoked VTE and 20 age- and sex-matched healthy controls recruited from the general population. Plasma levels, the cellular origin and the morphological characteristics of PSGL-1+ MVs were evaluated using flow cytometry, electron microscopy and confocal microscopy. Results Plasma levels of PSGL-1+ MVs were associated with increased risk of VTE. The odds ratio per one standard deviation increase in PSGL-1+ MVs was 3.11 (95% confidence interval [CI], 1.41-6.88) after adjustment for age and sex, and 2.88 (95% CI, 1.29-6.41) after further adjustment for body mass index. The PSGL-1+ MVs originated mainly from monocytes and endothelial cells determined by double staining with markers of parental cells using flow cytometry and transmission electron microscopy. Scanning electron microscopy of PSGL-1-labeled plasma-derived MVs displayed dominantly spherical vesicles that varied between 50 and 300 nm in diameter. Conclusions Increased plasma levels of PSGL-1+ MVs are associated with the risk of unprovoked VTE. Large population-based prospective studies are required to validate our findings.

Associations between complement pathways activity, mannose-binding lectin, and odds of unprovoked venous thromboembolism

IntroductionDeep vein thrombosis (DVT) originates in the valvular sinuses of large veins in a local milieu characterized by stasis and severe hypoxia. This may induce complement- and coagulation activation, which potentially increases the risk of venous thromboembolism (VTE). The aim of the present study was to investigate whether the activity of the complement pathways, the level of mannose-binding lectin (MBL) and tissue-factor (TF) induced thrombin generation were associated with risk of unprovoked VTE. MethodsA case-control study was performed in patients with unprovoked VTE (n = 24) and age- and sex-matched healthy controls (n = 24). Serum complement pathway activity was measured by the total complement screen assay (Wieslab®). MBL was quantified by ELISA. Plasma TF-induced thrombin generation was measured using the CAT-assay. ResultsActivity in the highest quintile of the classical pathway was associated with increased odds of unprovoked VTE (OR 4.5, 95% CI; 0.8–24.7). Moreover, MBL deficiency (≤100 ng/ml) was associated with unprovoked VTE (OR 3.5, 95% Cl; 0.8–15.3). VTE patients had shortened TF-induced lag-time (4.8 ± 0.6 min vs. 5.8 ± 2.1 min, p < 0.001) and a higher endogenous thrombin potential (ETP) (1383 ± 267 nM∗h vs. 1265 ± 247 nM∗h, p = 0.07) than controls. No association between the classical complement pathway activity or MBL deficiency, and parameters of TF-induced thrombin generation was observed. ConclusionOur findings suggest that high activity of the classical complement pathway, and MBL deficiency, might be associated with an increased odds of unprovoked VTE, independent of activation of TF-induced coagulation.

Nationwide study on the risk of unprovoked venous thromboembolism in non-traumatic osteonecrosis of femoral head.

Endothelial dysfunction is a risk factor for osteonecrosis of femoral head (ONFH) and venous thromboembolism (VTE) [defined as deep venous thrombosis (DVT) or pulmonary embolism (PE)]. However, the risk of unprovoked VTE in non-traumatic ONFH patients remains unclear. We investigated the relationship between ONFH and VTE using Taiwan National Health Insurance Research Database (NHIRD). Between 1997 and 2010, a total of 1514 non-traumatic ONFH patients were identified from 1,000,000 general populations after excluding initially concomitant diagnoses of DVT and PE, and subjects undergoing lower limb surgery within one year since enrollment. The comparison group (n = 15,140) without ONFH was set up by matching study cohort with age, gender, income and urbanization in a 1:10 ratio. Subjects diagnosed with VTE within one year after surgery were also excluded. The patients with non-traumatic ONFH had significantly higher frequency of unprovoked VTE, including DVT, than general population (1.19 vs. 0.5%, p < 0.0007), whereas the frequency of PE was similar between these two groups (p = 0.4922). The cumulative incidence of VTE and DVT was also remarkably higher in the ONFH than non-ONFH group (all p < 0.001). After adjusting for age, gender, medications and comorbidities with multivariate analysis, the ONFH patients had a 2.3-fold increase in risk of DVT compared with non-ONFH counterparts (95% CI 1.28 to 4.13, p = 0.0053). Apart from ONFH, age > 65years and hypertension were also identified as risk factors for DVT occurrence. The incidence and risk of unprovoked VTE were significantly increased in the non-traumatic ONFH population.

Cardiovascular fitness in young males and risk of unprovoked venous thromboembolism in adulthood

Background: Whether high cardiovascular fitness is associated with reduced risk of venous thromboembolism (VTE) is unknown. The present study aims to determine whether high cardiovascular fitness reduces the risk of VTE.Methods: A Swedish cohort of male conscripts (n = 773,925) born in 1954–1970 with no history of previous VTE were followed from enlistment (1972–1990) until 2010. Data on cardiovascular fitness using a cycle ergonometric test (maximal aerobic workload in Watt [Wmax]) at conscription were linked with national hospital register data and the Multi-Generation Register. We identified all full-siblings and first-cousin pairs discordant for maximal aerobic workload. This co-relative design allows for adjustment for familial resemblance.Results: In total, 3005 (0.39%) males were affected by VTE. Cardiovascular fitness estimated with Wmax was not associated with VTE risk when adjusted for body mass index (BMI). However, cardiovascular fitness estimated with Wmax/kg and adjusted for BMI was associated with reduced risk for VTE (Hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.78–0.85 per standard deviation compared with mean Wmax/kg). The association was weaker over time and also when examining discordant first cousins and full-sibling pairs.Conclusions: These results suggest that there is a relationship between cardiovascular fitness and weight that is important for future VTE risk.Key messagesWhether high cardiovascular fitness is associated with reduced risk of venous thromboembolism (VTE) is unknown.A Swedish cohort of male conscripts (n = 773,925) tested with a cycle ergometric test with no history of previous VTE were followed from enlistment (1972–1990) until 2010.Cardiovascular fitness estimated with Wmax/kg and adjusted for BMI was associated with reduced risk for VTE (HR 0.81, 95% CI 0.78–0.85).These results suggest that there is a relationship between cardiovascular fitness and weight that is important for future VTE risk.

Serum levels of 25(OH)D are not associated with venous thromboembolism in the elderly population. A case-control study.

The prevalence of both vitamin D deficiency and venous thromboembolism (VTE) is important in the elderly. Previous studies have provided evidence for a possible association between vitamin D status and the risk of VTE. Thus, we aimed to investigate the association between vitamin D levels and VTE in the population aged 75 and over included in the EDITH case-control study. The association between vitamin D status and VTE was analysed. We also analysed the monthly and seasonal variations of VTE and vitamin D. Between May 2000 and December 2009, 340 elderly patients (mean age 81.5 years, 32% men) with unprovoked VTE and their controls were included. The univariate and multivariate analysis found no significant association between serum levels of vitamin D and the risk of unprovoked VTE. In the unadjusted analysis, a higher BMI was statistically associated with an increased risk of VTE (OR 1.09; 95% CI 1.05-1.13) whereas a better walking capacity and living at home were associated with a decreased rate of VTE: OR 0.57; 95% CI 0.36-0.90 and 0.40; 95% CI 0.25-0.66, respectively. Although not significant, more VTE events occurred during winter (p=0.09). No seasonal variations of vitamin D levels were found (p=0.11). In conclusion, in contrast with previous reports our findings suggest that vitamin D is not associated with VTE in the elderly population.

Association between the metabolic syndrome, its individual components, and unprovoked venous thromboembolism: results of a patient-level meta-analysis.

The metabolic syndrome (MetS) may contribute to the pathogenesis of venous thromboembolism (VTE), but this association requires additional investigation. We performed a patient-level meta-analysis of case-control and cohort studies that evaluated the role of MetS and risk of unprovoked VTE. For case-control studies, odds ratios and 95% confidence intervals were calculated using logistic regression analysis to estimate the influence of individual variables on the risk of VTE; χ(2) tests for trend were used to investigate the effect of increasing number of components of MetS on the risk of VTE and to explore the influence of abdominal obesity on this relationship. For cohort studies, hazard ratios and 95% confidence interval were calculated using multivariable Cox regression analysis. Six case-control studies were included (908 cases with unprovoked VTE and 1794 controls): in multivariate analysis, MetS was independently associated with VTE (odds ratio, 1.91; 95% confidence interval, 1.57-2.33), and both MetS and abdominal obesity were better predictors of unprovoked VTE than obesity defined by the body mass index. Two prospective cohort studies were included (26,531 subjects and 289 unprovoked VTE events): age, obesity, and abdominal obesity, but not MetS were associated with VTE. Case-control but not prospective cohort studies support an association between MetS and VTE. Abdominal adiposity is a strong risk factor for VTE.

Cigarette smoking and the risk of venous thromboembolism: The Tromsø Study

Conflicting findings have been reported on the association between smoking and the risk of venous thromboembolism (VTE). To conduct a prospective, population-based cohort study to investigate the association between cigarette smoking and the risk of incident VTE. Information on smoking habits was assessed by self-administered questionnaires in 24 576 subjects, aged 25-96 years, participating in the fourth Tromsø Study in 1994-1995. Incident cases of VTE were registered until the end of follow-up at 1 September 2007. A total of 389 incident VTE events (1.61 per 1000 person-years) were registered during follow-up (median of 12.5 years). Heavy smokers (> 20 pack-years) had a hazard ratio (HR) of 1.46 (95% confidence interval [CI] 1.04-2.05) for total VTE, and and an HR of 1.75 (95% CI 1.14-2.69) for provoked VTE, as compared with never smokers. The risk of provoked VTE increased with more pack-years of smoking (P = 0.02). Smoking was not associated with risk of unprovoked VTE. The number of pack-years was associated with increased risk of cancer and myocardial infarction, whereas the association between pack-years of smoking and VTE disappeared when failure times were censored at the occurrence of cancer or myocardial infarction. Heavy smoking was apparently a risk factor for provoked VTE in analyses with VTE events as the only outcome. The lack of association between smoking and risk of VTE in analyses censored at the occurrence of cancer or myocardial infarction may suggest that smoking-attributable diseases or other predisposing factors are essential for smoking to convey a risk of VTE.

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

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. 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. A case-control study of 1401 patients with a first objectively-documented VTE and 1847 healthy controls has been carried out. 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. 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.

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.

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. 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. 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. 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.

Hematocrit and risk of venous thromboembolism in a general population. The Tromso study

Hematocrit above the normal range for the population, such as in primary or secondary erythrocytosis, predisposes to both arterial and venous thrombosis. However, little is known about the association between hematocrit and risk of venous thromboembolism in a general population. Hematocrit and related hematologic variables such as hemoglobin, red blood cell count, mean corpuscular volume, and baseline characteristics were measured in 26,108 subjects, who participated in the Tromsø Study in 1994-1995. Incident venous thromboembolic events during follow-up were registered up to September 1(st), 2007. There were 447 venous thromboembolic events during a median of 12.5 years of follow-up. Multivariable hazard ratios per 5% increment of hematocrit for the total population, adjusted for age, body mass index and smoking, were 1.25 (95% CI: 1.08-1.44) for total venous thromboembolism and 1.37 (95% CI: 1.10-1.71) for unprovoked venous thromboembolism. In category-based analyses, men with a hematocrit in the upper 20(th) percentile (>or=46% in men) had a 1.5-fold increased risk of total venous thromboembolism (95% CI: 1.08-2.21) and a 2.4-fold increased risk of unprovoked venous thromboembolism (95% CI: 1.36-4.15) compared to men whose hematocrit was in the lower 40(th) percentile. The risk estimates were higher for men than for women both in continuous and category-based analyses. The findings for hemoglobin and red blood cell count were similar to those for hematocrit, whereas mean corpuscular volume was not associated with venous thromboembolism. Conclusions Our findings suggest that hematocrit and related hematologic variables such as hemoglobin and red blood cell count are risk factors for venous thromboembolism in a general population.

Abstract 3613: Lipid Biomarkers, Hormone Therapy, and the Risk of Unprovoked Venous Thromboembolism in Women

Background : Published reports of a relationship between lipid biomarkers and venous thromboembolism (VTE) are inconsistent and controversial, and many do not account for potential effect modifiers such as hormone therapy (HT). Methods and Results : Among 27,082 initially healthy women followed prospectively (median, 11.4 years) for incident unprovoked VTE, we measured a full panel of lipid biomarkers, including total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, triglycerides, and apolipoproteins A-I (apo A-I) and B100. In analyses adjusted for age and body mass index (kg/m 2 ), only HDL-C and apo A-I showed any association with VTE (N=158; hazard ratio (95% CI) per 1 unit SD, 1.17 (1.00 –1.37) and 1.29 (1.11–1.51), respectively). However, after stratifying by HT use at the time of blood collection, none of the lipid biomarkers was associated with future VTE (N=80) in non-users, while higher levels of HDL-C and apo A-I were associated with increased risk of VTE (N=78) among users. Specifically, among HT users the adjusted hazard ratios for future VTE were 1.29 (1.05–1.58) and 1.41 (1.13–1.75) per 1 unit SD increase in HDL-C and apo A-I, respectively (each P≤0.01; Table ). In models further adjusted for factor V, prothrombin, and methylenetetrahydrofolate reductase genotypes, risk estimates did not change substantially, suggesting that the differences seen with HT were not due to any confounding by these genotypes. Conclusions : We observed little evidence that any lipid marker predicted risk of future VTE among non-users of HT. The observation that among HT users high levels of HDL-C and apo A-I relate to risk of VTE likely reflects concomitant prothrombotic effects of hormone therapy, rather than direct effects of HDL-C or apo A-I. Table. Risk of Future Unprovoked Venous Thromboembolism