In this work related to familial aggregation of familial venous thromboembolism, the investigators report genomic and transcriptomic association of 16 novel susceptibility loci for venous thromboembolism.

To cite this article: Braekkan SK, Mathiesen EB, Njølstad I, Wilsgaard T, Størmer J, Hansen JB. Family history of myocardial infarction is an independent risk factor for venous thromboembolism: the Tromsø study. J Thromb Haemost 2008; 6: 1851-7.Summary. Background: Recent studies indicate that arterial cardiovascular diseases and venous thromboembolism (VTE) share common risk factors. A family history of myocardial infarction (MI) is a strong and independent risk factor for future MI. Objectives: The purpose of the present study was to determine the impact of cardiovascular risk factors, including family history of MI, on the incidence of VTE in a prospective, population-based study. , 1.21; 95% CI, 1.13-1.31), and family history of MI (HR, 1.31; 95% CI, 1.04-1.65) were significantly associated with VTE. Family history of MI remained a significant risk factor for total VTE (HR, 1.27; 95% CI, 1.01-1.60) and unprovoked VTE (HR, 1.46; 95% CI, 1.03-2.07) in multivariable analysis. Blood pressure, total cholesterol, HDL-cholesterol, triglycerides, and smoking were not independently associated with total VTE. Conclusions: Family history of MI is a risk factor for both MI and VTE, and provides further evidence of a link between venous and arterial thrombosis.Keywords: atherosclerosis, family history, risk factors, venous thrombosis.Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common disease, with serious short-and long-term complications, and a potential fatal outcome [1]. It affects 1-3 per 1000 adults each year [1,2], and is the third most common cardiovascular disease [3]. Although surgery, trauma, hospitalization, malignancy, immobilization, pregnancy, use of oestrogens, and inherited thrombophilia are associated with VTE [1,4], approximately 30-50% of the events occur in the absence of obvious predisposing factors [5].The concept that VTE and atherosclerotic cardiovascular diseases are two distinct disease entities has recently been challenged. A higher frequency of carotid plaques in patients with idiopathic VTE has been reported [6]. The long-term incidence of cardiovascular disease is reported to be substantially increased in patients with VTE, compared to population controls [7]. A recent meta-analysis, based on selected prospective studies and case-control studies with verified endpoints, concluded that cardiovascular risk factors were associated with VTE [8]. However, prospective studies on the relation between traditional cardiovascular risk factors and VTE show diverging results. In the NursesÕ Health Study, obesity, cigarette smoking, and hypertension, but not diabetes or elevated cholesterol, were independent predictors for PE [9]. In the PhysiciansÕ Health Study [3], only body mass index (BMI) and height were identified as independent risk factors for VTE, whereas smoking and abdominal obesity were predictors for VTE in another study on middle-aged men [10]. In the LITE-study, obesity and diabetes, but not cigarette smoking, hypertension, and dysli...

Background-Lipopolysaccharide (LPS) is a major trigger of sepsis-induced disseminated intravascular coagulation (DIC) via the tissue factor (TF)/factor VIIa-dependent pathway of coagulation. Experimental endotoxemia has been used repeatedly to explore this complex pathophysiology, but little is known about the effects of clinically used anticoagulants in this setting. Therefore, we compared with placebo the effects of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) on LPS-induced coagulation. Methods and Results-In a randomized, double-blind, placebo-controlled trial, 30 healthy male volunteers received LPS 2 ng/kg IV followed by a bolus-primed continuous infusion of UFH, LMWH, or placebo. In the placebo group, activation of coagulation caused marked increases in plasma levels of prothrombin fragment F 1ϩ2 (PϽ0.01) and polymerized soluble fibrin, termed thrombus precursor protein (TpP; PϽ0.01); TF-positive monocytes doubled in response to LPS, whereas levels of activated factor VII slightly decreased and levels of TF pathway inhibitor remained unchanged. UFH and LMWH markedly decreased activation of coagulation caused by LPS, as F 1ϩ2 and TpP levels only slightly increased; TF expression on monocytes was also markedly reduced by UFH. TF pathway inhibitor values increased after either heparin infusion (PϽ0.01). Concomitantly, factor VIIa levels dropped by Ͼ50% at 50 minutes after initiation of either heparin infusion (PϽ0.01). Conclusions-This

Background Recent findings suggest that chronic kidney disease (CKD) may be associated with increased risk of venous thromboembolism (VTE). Given the high prevalence of mild-to-moderate CKD in the general population, in depth analysis of this association is warranted. Methods and Results We pooled individual participant data from five community-based cohorts from Europe (HUNT2, PREVEND and Tromsø study) and United States (ARIC and CHS study) to assess the association of estimated glomerular filtration rate (eGFR), albuminuria and CKD with objectively verified VTE. To estimate adjusted hazard ratios (HRs) for VTE, categorical and continuous spline models were fit using Cox regression with shared-frailty or random-effect meta-analysis. A total of 1,178 VTE events occurred over 599,453 person-years follow-up. Relative to eGFR 100 mL/min/1.73m2, HRs for VTE were 1.29 (95%CI, 1.04-1.59) for eGFR 75, 1.31 (1.00-1.71) for 60, 1.82 (1.27-2.60) for 45 and 1.95 (1.26-3.01) for 30 mL/min/1.73m2. Compared with albumin-creatinine ratio (ACR) of 5.0 mg/g, the HRs for VTE were 1.34 (1.04-1.72) for 30 mg/g, 1.60 (1.08-2.36) for 300 mg/g and 1.92 (1.19-3.09) for 1000 mg/g. There was no interaction between clinical categories of eGFR and ACR (P=0.20). The adjusted HR for CKD defined as eGFR <60 mL/min/1.73m2 or albuminuria ≥30 mg/g (vs. no CKD) was 1.54 (95%CI, 1.15-2.06). Associations were consistent in subgroups according to age, gender, and comorbidities as well as for unprovoked versus provoked VTE. Conclusions Both eGFR and ACR are independently associated with increased risk of VTE in the general population, even across the normal eGFR and ACR ranges.

Where expertise exists, endovascular therapy consisting of catheter-directed thrombolysis with angioplasty and stenting in selected cases could be considered as a primary therapeutic procedure in patients with acute postpartum DVT.

Objective The metabolic syndrome (MetS) may contribute to the pathogenesis of venous thromboembolism (VTE), but this association requires additional investigation. Approach and Results 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 (ORs) and 95% confidence intervals (CI) were calculated using logistic regression analysis to estimate the influence of individual variables on the risk of VTE; Chi squared tests for trend were used to investigate the impact 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 (HRs) and 95% CI were calculated by 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 (OR 1.91, 95% 1.57-2.33) and both MetS and abdominal obesity were better predictors of unprovoked VTE than obesity defined by the body mass index (BMI). Two prospective cohort studies were included (26.531 subjects, 289 unprovoked VTE events): age, obesity, and abdominal obesity, but not MetS were associated with VTE. Conclusions Case-control, but not prospective cohort studies support an association between MetS and VTE. Abdominal adiposity is a strong risk factor for VTE.

Anticoagulants have gained increasing attention in the treatment of sepsis. This study used danaparoid to investigate the role of factor Xa in endotoxin-induced coagulation and inflammation and its effectiveness when coagulation activation has already occurred. Thirty healthy volunteers were enrolled in the randomized, placebo-controlled trial. Subjects received 2 ng/kg endotoxin and danaparoid 10 min or 3 h thereafter or placebo. Endotoxin increased prothrombin fragment 1+2 (F(1+2)) levels from 0.5 to 7.0 nmol/L at 5 h in the placebo group. Early danaparoid infusion inhibited endotoxin-induced thrombin formation: maximum F(1+2) levels reached only 1.8 nmol/L (P<.01, vs. baseline or placebo). Delayed danaparoid infusion effectively blocked further thrombin formation. However, danaparoid did not alter endotoxin-induced changes in the fibrinolytic system, cytokine levels, activation of leukocytes, or tissue factor expression on monocytes. Danaparoid therefore selectively attenuates endotoxin-induced coagulopathy, even with delayed administration when coagulation activation is well under way.

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