Prospective study of homocysteine and MTHFR 677TT genotype and risk for venous thrombosis in a general population--results from the HUNT 2 study

This case‐cohort designed study prospectively investigated whether elevated homocysteine levels measured in blood samples drawn before the event and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (MTHFR C677T) were associated with subsequent first venous thrombosis (VT) in a general population. Between August 1995 and June 1997, blood was collected from 66 140 people in the second Norwegian Health Study of Nord‐Trøndelag (HUNT2). During a seven‐year follow‐up, 505 VT cases were identified. 1458 age‐ and sex‐matched controls were selected from the original cohort. Serum total homocysteine (tHcy) and MTHFR genotype were measured in stored samples that were drawn a median of 33 months before the events. The overall odds ratio (OR) was 1·50 [95% confidence interval (CI) 0·97–2·30] for homocysteine levels above versus below the 95th percentile. There was no graded association with VT over quintiles of homocysteine. In men the OR was 2·17 (95% CI 1·20–3·91) for levels above versus below the 95th percentile, but no association was found in women (OR 1·00). Stratification by age, predisposing risk factors or time to event did not change these results. The MTHFR 677TT genotype was not related to risk for VT. In conclusion, elevated homocysteine levels in the general population predicted subsequent first VT in men but not in women.     

High-density lipoprotein cholesterol and venous thromboembolism in the Longitudinal Investigation of Thromboembolism Etiology (LITE)

We determined prospectively the risk of venous thromboembolism (VTE) in relation to baseline high-density lipoprotein cholesterol (HDL-c) in 19 049 participants of the Longitudinal Investigation of Thromboembolism Etiology (LITE), which was composed of 14 490 participants of the Atherosclerosis Risk in Communities (ARIC) study and 4559 participants of the Cardiovascular Health Study (CHS). In addition, we determined the risk of VTE in relation to baseline subfractions of HDL (HDL(2) and HDL(3)) and apolipoprotein A-I (apoA-I) in 14 488 participants of the ARIC study. Age-adjusted incidence rates of VTE by HDL-c quartile ranged from 1.64 to 1.91 per 1000 person-years in men and 1.40 to 1.94 per 1000 person-years in women; however, there was no apparent trend of VTE incidence across HDL-c quartiles for either sex. The multivariate adjusted hazard ratios of VTE by HDL-c quartiles (with quartile 4 as the reference) were nonsignificant for both sexes and ranged between 0.91 and 0.99 for men and 0.78 and 1.22 for women. Results did not differ in separate evaluations of idiopathic and secondary VTE. In the ARIC study, there was no trend of VTE hazard ratios across quartiles of HDL(2), HDL(3), or apoA-I. Low HDL-c does not appear to be an important VTE risk factor.     

Reproductive history,hormone replacement,and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology

Numerous studies have established that hormone replacement therapy increases the risk of venous thromboembolism (VTE), but an association of endogenous oestrogen exposure with the incidence of VTE is not fully established. Using a prospective design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort, we studied the 12‐year risk of VTE in relation to hormone replacement therapy use, age at menopause, parity number, and type of menopause in 8236 post‐menopausal women. There were no significant associations of age at menopause, parity number, or type of menopause with incidence of VTE. Women currently using hormone replacement had a 1·6‐times higher multivariate‐adjusted rate ratio (RR) of VTE compared with those without hormone use in the time‐dependent model (RR = 1·60, 95% confidence interval [CI], 1·06–2·36; Population attributable fraction = 6·7%, 95%CI, 1·0–10·3). When we excluded women with 1‐year or more duration of hormone therapy at baseline, the association was stronger (RR = 2·02, 95%CI, 1·31–3·12). The multivariate‐adjusted RRs of VTE for current users tended to be higher in those with idiopathic VTE (RR = 2·40, 95%CI, 1·40–4·12) than those with secondary VTE (RR = 1·08, 95%CI, 0·63–1·85). Hormone replacement therapy is associated with increased risk of VTE, but reproductive history markers of endogenous oestrogen exposure were not associated with VTE.     

The Epidemiology of Venous Thromboembolism in the Community: Implications for Prevention and Management

The epidemiology of venous thromboembolism (VTE) in the community has important implications for VTE prevention and management. This review describes the incidence, survival, recurrence, complications and risk factors for deep vein thrombosis and pulmonary embolism occurring in the community. VTE incidence among whites of European origin exceeds 1 per 1000; the incidence among persons of African and Asian origin may be higher and lower, respectively. VTE incidence over recent time remains unchanged. Survival after VTE is worse than expected, especially for pulmonary embolism where one-quarter of patients present as sudden death. Of those patients who survive, 30% develop VTE recurrence and venous stasis syndrome within 10 and 20 years, respectively. Common independent VTE risk factors include surgery, hospitalization for acute medical illness, nursing home confinement, trauma, active cancer, neurologic disease with extremity paresis, superficial vein thrombosis, central venous catheter/transvenous pacemaker, and among women, oral contraceptives, pregnancy and the puerperium, and hormone and SERM therapy. Exposures can identify populations at risk but have a low predictive value for the individual person. An acquired or familial thrombophilia may predict the subset of exposed persons who actually develop symptomatic VTE. In conclusion, VTE is a common, lethal disease that recurs frequently and causes serious long-term complications. To improve survival and prevent complications, VTE occurrence must be reduced. Better individual risk stratification is needed in order to modify exposures and target primary and secondary prophylaxis to the person who would benefit most. Funded, in part, by grants from the National Institutes of Health (HL-60279, HL-66216, AR-30582) and Centers for Disease Control and Prevention (TS-326), U.S. Public Health Service; and by Mayo Foundation     

Prevalence of APC resistance and its relationship to arterial and venous thromboembolism in a general population sample of elderly Swedish men: The Study of Men Born in 1913

BACKGROUND: Most studies of hereditary resistance to activated protein C (APC resistance) as a risk factor for venous thromboembolism are derived from case-control studies of hospitalized patients, whilst the importance of this condition in the general population has been only sparsely investigated. OBJECTIVE: To study the prevalence of APC resistance and its relationship to morbidity and mortality in a general population sample of elderly men. DESIGN: Cross-sectional and prospective follow-up study. SETTING: General community: The Study of Men Born in 1913. SUBJECTS: A random population sample of 404 men, all 75 years of age. MAIN OUTCOME MEASURES: Four hundred and four men participated in a screening examination in 1988. The APC ratio was analysed in 382 of them. All the men were followed up for 5 years. Medical records were reviewed for all the men with a history of deep vein thrombosis, pulmonary embolism, myocardial infarction or stroke. RESULTS: Twenty-five men (6.5%) were found to have APC resistance. The incidence of venous thromboembolism, myocardial infarction or stroke did not differ between men with or without APC resistance, either retrospectively or during follow-up. Only two men experienced a deep vein thrombosis before the age of 80 and there was no case of pulmonary embolism. Mortality during 5 years of follow-up did not differ between men with and without APC resistance. CONCLUSION: The prevalence of APC resistance was 6.5% in this study of Swedish men. Although the size of the population sample is somewhat small, the study shows that, amongst elderly men, the association between APC resistance and venous thromboembolic disease was weak and men with this hereditary condition did not have any increase in morbidity or mortality compared with men without APC resistance.     

Prospective study of circulating factor XI and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE)

Elevated plasma concentrations of coagulation factor XI may increase risk of venous thromboembolism (VTE), but prospective data are limited. We studied prospectively the associations of plasma factor XI and a key F11 genetic variant with incident VTE in whites and African‐Americans. We measured factor XI in 16,299 participants, initially free of VTE, in two prospective population cohorts. We also measured the F11 single nucleotide polymorphism rs4241824, which a genome‐wide association study had linked to factor XI concentration. During follow‐up, we identified 606 VTEs. The age, race, sex, and study‐adjusted hazard ratio of VTE increased across factor XI quintiles (P < 0.001 for trend), and the hazard ratio was 1.51 (95% CI 1.16, 1.97) for the highest versus lowest quintile overall, and was 1.42 (95% CI 1.03, 1.95) in whites and 1.72 (95% CI 1.08, 2.73) in African‐Americans. In whites, the F11 variant was associated with both factor XI concentration and VTE incidence (1.15‐fold greater incidence of VTE per risk allele). In African‐Americans, these associations were absent. In conclusion, this cohort study documented that an elevated plasma factor XI concentration is a risk factor for VTE over extended follow‐up, not only in whites but also in African‐Americans. In whites, the association of the F11 genetic variant with VTE suggests a causal relation, but we did not observe this genetic relation in African‐Americans. Am. J. Hematol. 90:1047–1051, 2015. © 2015 Wiley Periodicals, Inc.     

Eustachian valve thrombus:critical factor in outcome of venous thromboembolism

This case report describes a patient with pulmonary embolism (PE) in whom transesophageal echocardiography showed a thrombus in the right atrium attached to the eustachian valve (EV). The EV is typically absent in the adult, but when present it is considered to be benign. It is an uncommon site for thrombus formation. This patient was treated with systemic anticoagulation.     

A comparison of three rapid D-dimer methods for the diagnosis of venous thromboembolism

We compared three rapid D-dimer methods for the diagnosis of venous thromboembolism. Patients presenting to four teaching hospitals with the possible diagnosis of deep vein thrombosis or pulmonary embolism were investigated with a combination of clinical likelihood, D-dimer (SimpliRED) and initial non-invasive testing. Patients were assigned as being positive or negative for deep vein thrombosis or pulmonary embolism based on their three-month outcome and initial test results. The three D-dimer methods compared were: (a) Accuclot D-dimer (b) IL-Test D-dimer (c) SimpliRED D-dimer. Of 993 patients, 141 had objectively confirmed deep vein thrombosis or pulmonary embolism. The sensitivity of SimpliRED, Accuclot and IL-Test were 79, 90 and 87% respectively. All three D-dimer tests gave similar negative predictive values. The SimpliRED D-dimer was found to be less sensitive than the Accuclot or IL-Test. When combined with pre-test probability all three methods are probably acceptable for use in the diagnosis of venous thromboembolism.     

Recent air travel and venous thromboembolism resulting in hospital admission

OBJECTIVE: The objective of the study was to determine the proportion of patients admitted to hospital with a deep vein thrombosis (DVT) or pulmonary embolism (PE) in whom recent air travel was documented in the medical records. METHODS: A retrospective review of the medical records of patients with a primary or secondary discharge diagnosis of DVT or PE in four hospitals in New Zealand was undertaken. From the medical records information was collected on demographic details, documentation of the presence of risk factors and results of radiological investigations. Strict radiological criteria were applied to ensure that the diagnosis of DVT or PE was firmly established. RESULTS: In 60 of 576 (10.4%) patients with a confirmed venous thromboembolism there was documentation of recent air travel; in 31 of these 60 subjects no other risk factors were recorded. In those cases in whom details of the air travel had been recorded, it had been undertaken in the previous 1 week in 65.0%, and in 43.3% the air travel was of at least 10-h duration. CONCLUSION: Long distance air travel is an important risk factor for venous thromboembolism requiring hospital admission and represents a significant public health problem in New Zealand.     

Management of venous thromboembolism – controversies and the future

Despite the availability of comprehensive evidence‐based guidelines there are difficult and controversial areas in the management of venous thromboembolism. Institutions and even countries disagree on the importance of calf vein thrombosis, with some rigorously detecting and treating it and others deliberately not looking for it. The need to treat proximal deep vein thrombosis and pulmonary embolism is accepted but which patients with an unprovoked first event should have long‐term anticoagulation has become a difficult clinical decision. We are uncertain how to reduce the incidence of post‐thrombotic syndrome seen in a substantial number of patients. How hard to look for an undiagnosed underlying cancer has become a contentious issue particularly in the United Kingdom following the recent publication of a guideline from the National Institute for Health and Clinical Excellence. Whilst we are wrestling with these dilemmas we are entering an era of new anticoagulants and have to solve the logistical problems of introducing them into clinical practice despite cost pressures. These issues will be explored in this review.     

Duration of anticoagulant therapy for venous thromboembolism: balancing benefits and harms on the long term

Venous thromboembolism (VTE) is effectively treated with anticoagulant therapy. After an initial treatment phase, extended treatment is effective to prevent recurrence after a first event but this is at the expense of a continued risk of bleeding. Ideally, patients at a high risk of recurrence and low risk of bleeding continue anticoagulant therapy, and for those at low risk of recurrence the duration of treatment can be limited. Identifying these patients, however, is difficult. Duration of treatment after a first VTE provoked by a transient risk factor should be limited to 3 months. Although guidelines suggest extended treatment for all patients after unprovoked VTE unless bleeding risk is high, we emphasize that the long-term risks of recurrent VTE off anticoagulation are uncertain whereas the risk of bleeding associated with anticoagulant therapy increases with age. In the absence of evidence of replaced mortality or improved quality of life with extended anticoagulant treatment, we suggest a limited duration for most patients after a first VTE. Extended treatment can be considered, based mainly on patient preference.     

Update on diagnosis and anticoagulant therapy for venous thromboembolism

Venous thromboembolism (VTE) continues to be a common medical problem requiring the need for rapid treatment with anticoagulant therapy. Until the recent availability of the direct oral anticoagulants for treatment of VTE, the option for oral anticoagulation was limited to warfarin therapy. The addition of these new medications has been welcomed, but has led to added complexities in deciding the most appropriate agent for each patient based on individual risk factors. Furthermore, there are several circumstances where optimal duration of therapy is not well established. This article will focus on the diagnosis of VTE, the choice of anticoagulant and treatment duration.     

Risk factors for venous thromboembolism (VTE) recurrences in Thai patients without cancer

Introduction: Studies in Western countries show that VTE recurrent rates are lower in the presence of a transient provoking factor, older age, female sex and/or hormonal use, while thrombophilia (factor V Leiden or prothrombin mutation) has no predictive role. This study aimed to determine the incidence and risk factors of recurrent VTE in Asian patients.

Method: This is a retrospective cohort study in adult VTE patients who were diagnosed during 2004–2014, had no active cancer and followed-up for at least 1 year.

Results: There were 198 patients. The mean age was 58.2?±?17.6 years and 68.2% were female. The diagnoses were deep vein thrombosis (56%), pulmonary embolism (32%) or both (12%). They were provoked by major surgery in 21.7%. Thrombophilia (antiphospholipid syndrome or protein C or protein S deficiency) was found in 11.6%. The recurrent rate during the median follow-up time of 52 months was 2.2 (95% confidence interval [CI] 1.46–3.31) per 100 patient-years. Presence of thrombophilia was independently associated with recurrences with the adjusted hazard ratio (aHR) of 3.52 (95% CI 1.32–9.42, p?=?0.01). There were 144 patients who discontinued anticoagulants. During the median time of 55 months after stopping anticoagulants, the recurrent rate was 4.3 per 100 patient-years. Thrombophilia was associated with recurrences with aHR of 4.00 (95% CI 1.42–11.31, p?=?0.01), while male sex, younger age, provoking conditions and hormone use showed no significant association.

Conclusion: VTE recurrent rate in Asians is comparable to Caucasians, but thrombophilia is the strongest risk factor.     

By word of mouse: using animal models in venous thrombosis research

Abstract

Deep vein thrombosis (DVT) is a disease with high prevalence and morbidity. It can lead to pulmonary embolism with severe respiratory insufficiency and risk of death. Mechanisms behind all stages of DVT, such as thrombosis commencement, propagation, and resolution, remain incompletely understood. Animal models represent an invaluable tool to explore these problems and identify new targets for DVT prevention and treatment. In this review, we discuss existing models of venous thrombosis, their advantages and disadvantages, and applicability to studying different aspects of DVT pathophysiology. We also speculate about requirements for an “ideal model” that would best recapitulate features of human DVT and discuss readouts of various models.     

Arterial cardiovascular risk factors and venous thrombosis: results from a population-based, prospective study (the HUNT 2)

Background

An explanation for the increased risk of myocardial infarction and stroke in patients with venous thrombosis is lacking. The objective of this study was to investigate whether risk factors for arterial cardiovascular disease also increase the risk of venous thrombosis.

Design and Methods

Cases who had a first venous thrombosis (n=515) and matched controls (n=1,505) were identified from a population-based, nested, case-cohort study (the HUNT 2 study) comprising 71% (n=66,140) of the adult residents of Nord-Trøndelag County in Norway.

Results

The age- and sex-adjusted odds ratio of venous thrombosis for subjects with concentrations of C-reactive protein in the highest quintile was 1.6 (95% confidence interval: 1.2–2.2) compared to subjects with C-reactive protein in the lowest quintile. This association was strongest in subjects who experienced venous thrombosis within a year after blood sampling with a three-fold increased risk of participants in the highest versus the lowest quintile. Having first degree relatives who had a myocardial infarction before the age of 60 years was positively associated with venous thrombosis compared to not having a positive family history [odds ratio 1.3 (95% confidence interval: 1.1–1.6)]. Subjects with blood pressure in the highest quintile had half the risk of developing venous thrombosis compared to subjects whose blood pressure was in the lowest quintile. There were no associations between the risk of venous thrombosis and total cholesterol, low density lipoprotein-cholesterol, high density lipoprotein-cholesterol, triglycerides, glucose or smoking. We confirmed the positive association between obesity and venous thrombosis.

Conclusions

C-reactive protein and a family history of myocardial infarction were positively associated with subsequent venous thrombosis. Blood pressure was inversely correlated to venous thrombosis. These findings should be confirmed by further investigations.