Indicators of lifetime endogenous estrogen exposure and risk of venous thromboembolism

BACKGROUND: Lifetime estrogen exposure has been related to breast cancer risk, osteoporosis, and cardiovascular disease but data on venous thromboembolism (VTE) risk are limited. METHODS: Data from a hospital-based case-control study among 608 postmenopausal women (191 with a first episode of idiopathic VTE and 417 age-matched controls) were used to determine whether estrogen exposure, as assessed by age at menopause [classified as early (< or = 45 years), normal (46-54 years) and late menopause (> or = 55 years)] and parity, was associated with the risk of VTE. RESULTS: After adjustment for potential confounding variables, the risk of VTE was increased with each year's delay in the menopause [odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.02-1.10, P < 0.0075]. When compared with women with normal menopause used as a reference, the adjusted OR for VTE was 0.59 (95% CI = 0.36-0.97) and 2.53 (95% CI = 1.28-4.99) for women with early menopause and late menopause, respectively (P = 0.001). Adjusted OR for VTE was also higher for women with more than two children when compared with those with less than or equal to two children (1.56, 95% CI = 1.03-2.34, P = 0.03). The lowest risk of VTE was observed in women with early menopause and lower parity (adjusted OR = 0.60, 95% CI = 0.30-1.24), the highest risk was among women with late menopause who have had more than two children (adjusted OR = 3.41, 95% CI = 1.46-9.25). CONCLUSION: These results show that the longer exposure to endogenous estrogen is associated with an increased VTE risk.     

Lipid biomarkers, hormone therapy and the risk of venous thromboembolism in women

Summary.  Background: Published reports of a relationship between lipids and incident venous thromboembolism (VTE) are conflicting. Objectives: To clarify the relationship between lipids and VTE risk in healthy women, including potential effect modification by hormone therapy (HT). Patients/methods: Among 27 081 initially healthy women followed prospectively for incident VTE, we measured a full panel of lipid biomarkers, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides and apolipoproteins A-I (apo A-I) and B₁₀₀. Results: During a median follow-up of 11.4 years, VTE occurred in 355 women. We observed no relationship between any of the lipids and VTE risk. However, when unprovoked VTE was considered separately ( n  = 161), both HDL-C and apo A-I were positively associated with risk. Fully adjusted hazard ratios (HR) and 95% confidence intervals (CI) for extreme tertiles of HDL-C and apo A-I were 1.75 (1.13–2.73) and 1.70 (1.10–2.62), respectively. After stratifying by HT use, this relationship was present only among HT users; the HRs for unprovoked VTE for extreme tertiles of HDL-C and apo A-I were 3.58 (1.69–7.58) and 2.88 (1.29–6.42) among users, but only 0.79 (0.39–1.62) and 0.89 (0.50–1.57) among non-users. The interactions were statistically significant (each P _interaction <0.05). Conclusions: We observed little evidence that lipid levels predict risk of incident VTE among non-users of HT. High levels of HDL-C and apo A-I associate with unprovoked VTE risk among HT users. This observation likely reflects prothrombotic effects of HT that are concomitant with HDL-C and apo A-I levels, rather than direct effects of those lipids.     

Factor V Leiden and venous thromboembolism: risk associated with hormone replacement therapy

PURPOSE: To determine the risk-benefit ratio of hormone replacement therapy (HRT) and the cost-effectiveness of screening in perimenopausal and postmenopausal women who are carriers of factor V Leiden, as well as to provide evidence-based clinical recommendations for the primary care provider. DATA SOURCES: Databases searched included EMBASE, BIOSIS, MEDLINE, CINAHL, PubMed, SciSearch, and the Cochrane Database. Two reviewers extracted, reviewed, and concurred upon relevant evidence identified in the data-bases. RESULTS: Results confirmed that all women have a higher risk for the development of venous thrombosis while on HRT. The presence of a genetic mutation, such as factor V Leiden, in combination with HRT dramatically increased an individual's chance for developing venous thrombi. CONCLUSION/IMPLICATIONS: Based on the findings of the studies reviewed, it is recommended that women wishing to initiate HRT be thoroughly screened for known risk factors of thrombosis. If risk factors are identified, genetic testing for factor V Leiden may be warranted.     

Metabolic syndrome and risk of venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology

Summary.  Background:  In a recent case–control study, the odds of metabolic syndrome (MetSyn) among deep vein thrombosis cases were almost twice those among controls. We tested the hypothesis that the incidence of non-cancer-related venous thromboembolism (VTE) is higher among adults with MetSyn and further, that associations are stronger for idiopathic than secondary VTE. Methods:  A total of 20 374 middle-aged and elderly adults were followed for over 12 years for incident VTE in the Longitudinal Investigation of Thromboembolism Etiology (LITE). All hospitalizations were identified and VTEs validated by chart review. Baseline MetSyn was defined using ATP III guidelines, including ≥3 of the following components: abdominal obesity, elevated blood pressure, low HDL-cholesterol, high triglycerides and high glucose. Because sex modified the relation between MetSyn and VTE (p_interaction = 0.001), proportional hazards regression analyses were stratified by sex to assess the associations of MetSyn and its components with risk of incident non-cancer-related VTE, adjusting for potential confounders. Results:  Incident VTE ( n  = 358) included 196 idiopathic events. Baseline MetSyn was associated with risk of total VTE (hazard ratio (HR) = 1.84, 95% CI = 1.30, 2.59) and idiopathic VTE (HR = 1.59, 95% CI = 1.02, 2.47) among men, but not women. The association was largely attributable to abdominal obesity (HR of VTE = 2.10, 95% CI = 1.51, 2.93, in men; HR of VTE = 1.70, 95% CI = 1.24, 2.34, in women), with no additional contribution by the other MetSyn components. Conclusion:  Although abdominal obesity was associated with increased risk of VTE in both men and women, MetSyn and its other components do not seem important in VTE etiology.     

Oral contraceptives and venous thromboembolism: identifying the safest option

Evaluation of: van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJM, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case–control study. BMJ 339, b2921 (2009).

Women who use combined oral contraceptives containing estrogen and progestogen have an associated two- to eight-fold increased risk of venous thromboembolism. Over the years, in an attempt to reduce the associated venous thrombotic risk, newer preparations of oral contraceptives containing lower doses of estrogen and different types of progestogens have been introduced. The article under evaluation has quantified and further examined this association according to the dose of estrogen and the type of progestogen in oral contraceptives, in a large cohort of premenopausal women in The Netherlands. The results showed that oral contraceptive preparations that contain levonorgestrel and those that contain a low-dose estrogen were associated with lower risk than preparations containing other types of progestogens (including newer preparations, such as cyproterone acetate and drospirenone) and a greater estrogen dose, respectively.     

Hormone replacement therapy and the risk of venous thromboembolism: a population‐based study

Summary. Background: Hormone replacement therapy (HRT) using oral estrogen alone or combined with a progestogen is associated with an increased risk of venous thromboembolism (VTE) in postmenopausal women. This risk may differ for tibolone and transdermal HRT. Methods: Among the United Kingdom’s General Practice Research Database, we identified the cohort of all women aged 50–79 between 1 January 1987 and 1 March 2008. Using a nested case–control approach, all incident cases of VTE occurring during the study period were identified and matched with up to 10 controls selected from the cohort members. Rate ratios (RR) of VTE with current use of tibolone, transdermal and oral HRT were estimated using conditional logistic regression. Results: The cohort of 955 582 postmenopausal women included 23 505 cases of VTE matched with 231 562 controls. The risk of VTE was not increased with current use of transdermal estrogen alone (RR 1.01; 95% CI, 0.89–1.16) or combined with a progestogen (RR 0.96; 95% CI, 0.77–1.20), or with current use of tibolone (RR 0.92; 95% CI: 0.77–1.10), relative to non‐use. On the other hand, the risk was increased with current use of oral estrogen (RR 1.49; 95% CI, 1.37–1.63) and oral estrogen–progestogen (RR 1.54; 95% CI, 1.44–1.65), and increased with estrogen dosage. The risks with oral formulations were particularly elevated during the first year of use but disappeared 4 months after discontinuation. Conclusion: Transdermal HRT and tibolone were not associated with an increased risk of VTE in postmenopausal women.     

The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy

Roach REJ, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost 2013; 11 : 124–31. Summary. Background: Oral contraception (OC) and postmenopausal hormone therapy (HT) can be used to alleviate menopausal symptoms. However, the risk of venous thrombosis (VT) associated with OC use in women over 50 years old has never been assessed and the two preparations have not been directly compared. Objectives: To determine and compare the risk of VT associated with OC and HT use. Methods: From a large case–control study, 2550 women aged over 50 years old, 1082 patients with a first VT and 1468 controls, were included. Odds ratios (ORs) and 95% confidence intervals for VT were calculated for OC‐users (164 patients and 54 controls) and HT‐users (88 patients and 102 controls) compared with non‐hormone users (823 patients and 1304 controls). Results: OC‐users had a 6.3‐fold (4.6–9.8) increased risk of VT. This ranged from 5.4 (3.3–8.9) for preparations containing levonorgestrel to 10.2 (4.8–21.7) for desogestrel. The VT‐risk associated with oral HT use was 4.0 (1.8–8.2) for conjugated equine estrogen combined with medroxyprogesterone acetate and 3.9 (1.5–10.7) for micronized estradiol combined with norethisterone acetate. Non‐oral HT did not increase the risk of VT: OR 1.1 (0.6–1.8). Relative risk estimates were further increased in hormone users with factor V Leiden, prothrombin G20210A or blood group non‐O and hormone users with a family history of VT. Conclusions: In this study, non‐oral HT seemed to be the safest hormonal preparation in women over 50 years old. OC use increased the VT risk the most, especially in women with inherited thrombophilia or a family history of VT.     

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

Summary. Background: Conflicting findings have been reported on the association between smoking and the risk of venous thromboembolism (VTE). Objectives: To conduct a prospective, population‐based cohort study to investigate the association between cigarette smoking and the risk of incident VTE. Patients/Methods: 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. Results: 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. Conclusions: 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.     

The incidence of venous thromboembolism among Factor V Leiden carriers: a community-based cohort study

While Factor V (FV) Leiden is a risk factor for venous thromboembolism (VTE), the incidence of VTE among FV Leiden carriers is uncertain. The objective of the study was to estimate the overall age-specific and pregnancy-related VTE incidence and the relative risk among FV Leiden carriers. In a community-based sample of 3424 south-eastern Minnesota residents, 230 (6.7%) were genotyped as FV Leiden carriers; 220 carriers (mean age = 68 years) could be matched to a non-carrier on age, gender, ethnicity and length of medical history. We performed a retrospective cohort study of carriers and non-carriers by reviewing the complete medical records in the community for demographic and baseline characteristics, pregnancies and live births, and first lifetime VTE. Over 14 722 person-years, 24 (10.9%) carriers developed VTE [overall incidence = 163 (95% CI 104, 242) per 100,000 person-years]. VTE incidence rates for ages 15-29, 30-44, 45-59 and > or = 60 years were 0, 61, 244 and 764 per 100,000 person-years, respectively (cumulative VTE incidence at age 65 years = 6.3%). VTE incidence for carriers did not differ significantly from that for non-carriers except for those > or = 60 years old (relative risk = 3.6; 95% CI 2.0, 6.0). There were 311 live births among 130 women carriers; no VTE events occurred during pregnancy or postpartum [incidence = 0 (95% CI 0, 1186) per 100,000 women-years]. Most FV Leiden carriers do not develop VTE. Among all carriers, those > or = 60 years old are at the highest risk for VTE. The incidence of VTE among asymptomatic women carriers during pregnancy is low and insufficient to warrant prophylaxis.     

Familial risk of venous thromboembolism: a nationwide cohort study

Background: Venous thromboembolism has genetic determinants, but population‐based data on familial risks are limited. Objectives: To examine the familial risk of venous thromboembolism. Methods: We undertook a nationwide study of a cohort of patients with deep venous thrombosis or pulmonary embolism born after 1952. We used the Danish National Registry of Patients covering all Danish hospitals, for the years 1977 through 2009, to identify index cases of venous thromboembolism, and assessed the incidence among their siblings. We compared standardized incidence ratios (SIRs) of the observed and expected number of venous thromboembolism cases among siblings, using population‐specific, gender‐specific and age‐specific incidence rates. Results: We identified 30 179 siblings of 19 599 cases of venous thromboembolism. The incidence among siblings was 2.2 cases per 1000 person‐years, representing a relative risk of 3.08 (95% confidence interval [CI] 2.80–3.39) as compared with the general population. The risk was higher for both men (SIR 3.36, 95% CI 2.96–3.82) and women (SIR 2.81, 95% CI 2.45–3.23). The risk was similar among siblings of index cases with venous thrombosis and those of index cases with pulmonary embolism. Conclusion: Venous thromboembolism has a strong familial component.     

Coffee consumption and the risk of venous thromboembolism: the Tromsø study

Summary. Background: Several studies have investigated the association between coffee consumption and cardiovascular disease, but little is known about coffee intake and the risk of venous thromboembolism (VTE). Objective: The aim of this prospective cohort study was to investigate the association between coffee consumption and the risk of incident VTE in a general population. Methods: Information about coffee consumption habits was obtained with a self‐administered questionnaire in 26 755 subjects, aged 25–97 years, who participated in the fourth survey of the Tromsø study (1994–1995). Incident VTE events were registered until the end of follow‐up, 1 September 2007. Results: There were 462 incident VTE events (1.60 per 1000 person‐years, 95% confidence interval [CI] 1.46–1.75) during a median of 12.5 years of follow‐up. A daily consumption of three to four cups was borderline associated (hazard ratio [HR] 0.70; 95% CI 0.48–1.02) and a daily consumption of five to six cups (HR 0.67; 95% CI 0.45–0.97) was significantly associated with reduced risk of VTE as compared with coffee abstainers in multivariable analysis adjusted for age, sex, body mass index (BMI), smoking status, physical activity, diabetes, history of cardiovascular disease and cancer. Similar risk estimates were found for provoked and unprovoked VTE, and in sex‐stratified analyses. Conclusion: Our findings suggest a possible U‐shaped relationship between coffee consumption and VTE, and that moderate coffee consumption may be associated with a reduced risk of VTE. However, more studies are needed to establish whether moderate coffee consumption is inversely associated with the risk of VTE.     

The role of genetics in the risk of thromboembolism: prothrombin 20210A and oral contraceptive therapy

PURPOSE: To provide an overview of the prothrombin 20210A mutation, its effects on the incidence of venous thromboembolism (VTE) in users of oral contraceptive therapy (OCT), and screening recommendations for the primary care practice setting. DATA SOURCES: Several databases, including MEDLINE, EMBASE, BIOSIS, Cochrane Library, and SciSearch, were searched for articles published between 1996 and 2003. An integrative review of studies addressing prothrombin 20210A was done using available case-series and case-control studies. No randomized controlled trials on prothrombin 20210A were available in the literature from the years searched. CONCLUSIONS: Prothrombin 20210A increases the risk of developing a VTE for those who carry the genetic mutation. The presence of either concomitant circumstantial factors (e.g., surgery or immobilization) or a combination of genetic factors (e.g., factor V Leiden and prothrombin 20210A) raises the frequency of VTEs to an even greater extent. The risk increases exponentially in users of OCT. Screening guidelines for the use of OCT in prothrombin 20210A carriers remain unclear due to the paucity of empirical evidence related to the topic. IMPLICATIONS FOR PRACTICE: Practitioners caring for a prothrombin 20210A carrier should maintain a high degree of suspicion with even vague signs or symptoms of a possible VTE. Practitioners should consider completing a full diagnostic workup for VTE on that patient, particularly if that patient is taking OCT. Until evidence becomes available as to the best anticoagulation practice after an initial or recurrent VTE in a prothrombin 20210A carrier, standard treatment guidelines for anticoagulation should be followed.     

The incidence,risk factors and prognostic implications of venous thromboembolism in patients with gastric cancer

Summary. Background: Data on venous thromboembolism (VTE) in gastric cancer (GC) are very scarce. Objective: To investigate the incidence, risk factors and prognostic implications of VTE in Asian GC patients. Methods: Prospective databases containing clinical information on GC patients (n = 2,085) were used. Results: The 2‐year cumulative incidences of all VTE events were 0.5%, 3.5% and 24.4% in stages I, II–IV(M0) and IV(M1), respectively. Advanced stage, older age and no major surgery were independent risk factors for developing VTE. When the VTE cases were classified into extremity venous thrombosis (EVT), pulmonary thromboembolism (PTE) or intra‐abdominal venous thrombosis (IVT), IVTs (62%) were more common than EVTs (21%) or PTEs (17%). Although peri‐operative pharmacologic thromboprophylaxis was not routinely administered, the VTE incidence after major surgery was only 0.2%. During chemotherapy, EVT/PTE developed more frequently than IVT (54% vs. 19%); however, during untreated or treatment‐refractory periods, IVT developed more frequently than EVT/PTE (69% vs. 36%). In multivariate models, the development of EVT/PTE was a significant predictor of early death when compared with no occurrence of VTE (P < 0.05). However, IVT did not affect survival. Conclusion: This is the largest study that specially focused on VTE in GC and the VTE incidence in Asian GC patients was first demonstrated. Considering the low incidence of post‐operative VTE development, the necessity of peri‐operative pharmacologic thromboprophylaxis should be evaluated separately in Asian patients. The clinical situation of the development of EVT/PTE and IVT differed. Only EVT/PTE had an adverse effect on survival and IVT had no prognostic significance.     

The G20210A prothrombin variant and the risk of venous thromboembolism or fetal loss in pregnant women: a family study

BACKGROUND: The relationship between the G20210A prothrombin variant (PT-G20210A) and adverse pregnancy outcome has been studied by several groups in the last few years. However, because of the different design and sample sizes of these studies the estimated risks have varied. OBJECTIVE: In this retrospective, multi-center, cohort study we assessed the risk of thromboembolic or obstetric complications in women belonging to families of probands with isolated PT-G20210A and that were symptomatic for venous thromboembolism (VTE). METHODS: Two hundred and eighty-three female family members that had been pregnant at least once were enrolled. The occurrence of VTE and obstetric complications during pregnancy and postpartum were assessed in carriers of PT-G20210A and compared with non- carriers. RESULTS: One thromboembolic event occurred during the postpartum period in the carriers group. In the same group, 48 out of 359 pregnancies resulted in unexplained fetal loss as compared with 50 out of 357 pregnancies in the non-carriers (RR 0.9; 95% CI: 0.7-1.4). After adjustment, carriers of PT-G20210A showed a trend towards a higher risk of late fetal loss as compared with non-carriers (RR 2.2; 95% CI: 0.8-6.2). Furthermore, in pregnancies subsequent to those with previous fetal loss there was not a different risk of adverse outcome regardless of the carrier status. CONCLUSIONS: Female family members who are heterozygous carriers of isolated PT-G20210A do not seem to be at significant increased risk for fetal loss as compared with non-carriers. Screening for PT-G20210A of fertile age women belonging to these families is not warranted in this situation.     

Fatal bleeding in patients receiving anticoagulant therapy for venous thromboembolism: findings from the RIETE registry

Summary. Background: Fatal bleeding is a serious consequence of anticoagulant therapy, but factors associated with fatal bleeding during the first 3 months of treatment of venous thromboembolism (VTE) are uncertain. Methods: Using data from RIETE, an ongoing registry of consecutive patients with acute VTE, we assessed risk factors for fatal bleeding among all patients. We then used this information to derive a clinical model that would stratify a patient’s risk of fatal bleeding during the first 3 months of treatment. Results: Of 24 395 patients, 546 (2.24%) had a major bleed and 135 (0.55%) had a fatal bleed. The gastrointestinal tract was the most common site (40% of fatal bleeds), followed by intracranial bleeding (25%). Fatal bleeding was independently associated with the following factors at the time of VTE diagnosis: age >75 years (OR, 2.16), metastatic cancer (OR, 3.80), immobility ≥ 4 days (OR, 1.99), a major bleed within the past 30 days (OR, 2.64), an abnormal prothrombin time (OR, 2.09), a platelet count < 100 × 10⁹ L⁻¹ (OR, 2.23), creatinine clearance < 30 mL min⁻¹ (OR, 2.27), anemia (OR, 1.54), and distal deep vein thrombosis (OR, 0.39). INR at the time of bleeding is not known. A clinical prediction rule for risk of fatal bleeding that included nine baseline factors was derived. Fatal bleeding occurred in 0.16% (95% CI, 0.11–0.23) of the low‐risk, 1.06% (95% CI, 0.85–1.30) of the moderate‐risk, and 4.24% (95% CI, 2.76–6.27) of the high‐risk category. Conclusions: Patient characteristics and laboratory variables can identify patients at high risk for fatal bleeding during treatment of VTE.