Elevated plasma fibronectin levels associated with venous thromboembolism

Elevated plasma fibronectin levels occur in various clinical states including arterial disease. Increasing evidence suggests that atherothrombosis and venous thromboembolism (VTE) share common risk factors. To assess the hypothesis that high plasma fibronectin levels are associated with VTE, we compared plasma fibronectin levels in the Scripps Venous Thrombosis Registry for 113 VTE cases vs. age and sex matched controls. VTE cases had significantly higher mean fibronectin concentration compared to controls (127% vs. 103%, p<0.0001); the difference was greater for idiopathic VTE cases compared to secondary VTE cases (133% vs. 120%, respectively). Using a cut-off of >90% of the control values, the odds ratio (OR) for association of VTE for fibronectin plasma levels above the 90th percentile were 9.37 (95% CI 2.73-32.2; p<0.001) and this OR remained significant after adjustment for sex, age, body mass index (BMI), factor V Leiden and prothrombin nt20210A (OR 7.60, 95% CI 2.14-27.0; p=0.002). In particular, the OR was statistically significant for idiopathic VTE before and after these statistical adjustments. For the total male cohort, the OR was significant before and after statistical adjustments and was not significant for the total female cohort. In summary, our results suggest that elevated plasma fibronectin levels are associated with VTE especially in males, and extend the potential association between biomarkers and risk factors for arterial atherothrombosis and VTE. © 2008 Schattauer GmbH.

High-density lipoprotein and the risk of recurrent venous thromboembolism

BACKGROUND - High-density lipoprotein (HDL) protects against arterial atherothrombosis, but it is unknown whether it protects against recurrent venous thromboembolism. METHODS AND RESULTS - We studied 772 patients after a first spontaneous venous thromboembolism (average follow-up 48 months) and recorded the end point of symptomatic recurrent venous thromboembolism, which developed in 100 of the 772 patients. The relationship between plasma lipoprotein parameters and recurrence was evaluated. Plasma apolipoproteins AI and B were measured by immunoassays for all subjects. Compared with those without recurrence, patients with recurrence had lower mean (±SD) levels of apolipoprotein AI (1.12±0.22 versus 1.23±0.27 mg/mL, P<0.001) but similar apolipoprotein B levels. The relative risk of recurrence was 0.87 (95% CI, 0.80 to 0.94) for each increase of 0.1 mg/mL in plasma apolipoprotein AI. Compared with patients with apolipoprotein AI levels in the lowest tertile (<1.07 mg/mL), the relative risk of recurrence was 0.46 (95% CI, 0.27 to 0.77) for the highest-tertile patients (apolipoprotein AI >1.30 mg/mL) and 0.78 (95% CI, 0.50 to 1.22) for midtertile patients (apolipoprotein AI of 1.07 to 1.30 mg/mL). Using nuclear magnetic resonance, we determined the levels of 10 major lipoprotein subclasses and HDL cholesterol for 71 patients with recurrence and 142 matched patients without recurrence. We found a strong trend for association between recurrence and low levels of HDL particles and HDL cholesterol. CONCLUSIONS - Patients with high levels of apolipoprotein AI and HDL have a decreased risk of recurrent venous thromboembolism. © 2007 American Heart Association, Inc.

Is adiponectin implicated in venous thromboembolism?

In summary, these results imply that the relationship of adiponectin with lipoproteins is more complex than previously predicted using other methods of lipoprotein fractionation. Higher correlation of adiponectin was shown with large lipoprotein particle size, independent of the apolipoprotein content. Given the small population studied, we could not assess the influence of mild risk factors for venous thrombosis, such as obesity, on the analysis of the results. Thus, we can only state that adiponectin levels appear not to be a strong risk factor for VTE. It is possible that adiponectin deficiency may contribute indirectly to the etiology of VTE by enhancing the inflammatory state. © 2006 International Society on Thrombosis and Haemostasis.

Apixaban for the prevention of thromboembolism in adults after elective hip or knee replacement surgery, and in symptomatic venous thromboembolism

The anticoagulant effect of apixaban is due to direct inhibition of FXa in the coagulation cascade. The main advantages apixaban has over the current anti-coagulant drugs is that it is active after oral administration, and its coagulation effect does not require monitoring. Apixaban has been compared to enoxaparin in the prevention of venous thromboembolism associated with knee and hip replacement, where it is as efficacious as enoxaparin, but causes less bleeding. However, apixaban is not the only FXa inhibitor that could replace enoxaparin for this indication, as the FXa inhibitor rivaroxaban is as efficacious and safe as enoxaparin in preventing thromboembolism associated with these surgical procedures. Until the results of the AMPLIFY Phase III trial are known, it is too early to consider apixaban as an alternative to enoxaparin in symptomatic thromboembolism. Apixaban should not be used to prevent thromboembolism in medical immobilised subjects or acute coronary syndromes, as it causes excess bleeding in these conditions without benefit.

Pharmacist prescribing of venous thromboembolism prophylaxis in a surgical pre-admission clinic

Venous thromboembolism (VTE) is the term used to describe the disease process which presents as either deep vein thrombosis or pulmonary embolism. It is a major cause of death and disability worldwide and places a large financial burden on healthcare systems. Multiple risk factors have been identified for the development of VTE, including hospitalisation for acute medical illness and surgery. Documentation of VTE risk assessment is a critical part of any patient admission, driven by evidence that a risk assessment is a trigger for VTE prophylaxis to be considered. In the United Kingdom, healthcare services have set targets for VTE risk assessment documentation and financial incentives are linked to targets being met...

Venous thromboembolism during pregnancy and the impact of thrombophilia in pregnancy complications

Venous thromboembolism (VTE) is the greatest single cause of maternal mortality in pregnant women in developed countries. Pregnancy is a hypercoagulable state and brings about an enhanced risk of deep venous thrombosis (DVT) in otherwise healthy women. Traditionally, unfractionated heparin (UFH) has been used for treatment of DVT during pregnancy. We showed in our observational study that low molecular weight heparin (LMWH) is as effective and safe as UFH in the treatment of DVT during pregnancy. Although DVT during pregnancy is often massive, increasing the risk of developing long-term consequences, namely post-thrombotic syndrome (PTS), only 11% of all patients had confirmed PTS 3 4 years after DVT. In our studies the prevalence of PTS was not dependent on treatment (UFH vs LMWH). Low molecular weight heparin is more easily administered, few laboratory controls are required and the hospital stay is shorter, factors that lower the costs of treatment. Cervical insufficiency is defined as repeated very preterm delivery during the second or early third trimester. Infection is a well-known risk factor of preterm delivery. We found overpresentation of thrombophilic mutations (FV Leiden, prothrombin G20210A)among 42 patients with cervical insufficiency compared with controls (OR 6.7, CI 2.7 18.4). Thus, thrombophilia might be a risk factor of cervical insufficiency possibly explained by interaction of coagulation and inflammation processes. The presence of antiphospholipid (aPL) antibodies increases the risk for recurrent miscarriage (RM). Annexins are proteins which all bind to anionic phospholipids (PLs) preventing clotting on vascular phospholipid surfaces. Plasma concentrations of circulating annexin IV and V were investigated in 77 pregnancies at the beginning of pregnancy among women with a history of RM, and in connection to their aPL antibody status. Control group consisted unselected pregnant patients (n=25) without history of adverse pregnancy outcome. Plasma levels of annexin V were significantly higher at the beginning (≤5th week) of pregnancy in women with aPL antibodies compared with those without aPL antibodies (P=0.03). Levels of circulating annexin V were also higher at the 6th (P= 0.01) and 8th week of pregnancy in subjects with aPL antibodies (P=0.01). Results support the hypothesis that aPL could displace annexin from anionic phospholipid surfaces of syncytiotrophoblasts (STBs) and may exert procoagulant activities on the surfaces of STBs Recurrent miscarriage (RM) has been suggested to be caused by mutations in genes coding for various coagulation factors resulting in thrombophilia. In the last study of my thesis were investigated the prevalence of thrombomodulin (TM) and endothelial protein C receptor polymorphism EPCR among 40 couples and six women suffering RM. This study showed that mutations in the TM or EPCR genes are not a major cause of RM in Finnish patients.

Thromboembolism and bleeding in bladder cancer.

Bladder cancer is a unique disease process in that clinically significant hemorrhage can occur simultaneously with equally significant aberrant clotting. With hematuria the key presenting symptom of bladder cancer, hemorrhage is generally thought to be a component of the natural history of the disease, and to commonly occur during its treatment. However, as those who regularly treat bladder cancer know, the need to address a predisposition to clotting is also very much part of the treatment paradigm. Physicians must be cognizant of the biochemical changes that confer a propensity for both significant bleeding and clotting occurring simultaneously in their patients. Both of these entities remain important issues, and further study is needed to find ways to mitigate and balance the associated risks. Here, we performed a review of the literature, focusing on the concomitant issues of bleeding and venous thromboembolism in both the pre- and post-operative periods in patients with bladder cancer. We formulated a general management approach with respect to these two processes, and we provide direction for further investigation.

The pathogenesis of venous thromboembolism in cancer: emerging links with tumour biology.

Venous thromboembolism (VTE) is a frequent complication in individuals with cancer and is considered to be a cause of substantial mortality. Epidemiological studies identify malignancy as an independent VTE risk factor and show that cancer patients are at increased risk of both initial and recurrent VTE events. The risk due to cancer is compounded by the effects of chemotherapy and other treatments. The pathogenesis of cancer-associated VTE is complex involving multiple interactions between tumours and various components of haemostasis. The development of a systemic hypercoagulable state is considered a key pathogenetic feature and is attributed to tumour expression of tissue factor and other procoagulants, activation of vascular cells by tumour-derived cytokines and adhesive interactions between tumour cells and host cells. An increasing body of evidence indicates that the activation of haemostasis in malignant disease contributes to tumour growth and progression by stimulation of intracellular signalling pathways. The interaction of tissue factor, thrombin and other coagulation factors with protease activated receptor (PAR) proteins expressed by tumour cells and host vascular cells leads to the induction of genes related to the processes of angiogenesis, cell survival and cell adhesion and migration.

Cost-effectiveness of low-molecular-weight heparin for secondary prophylaxis of cancer-related venous thromboembolism.

Although extended secondary prophylaxis with low-molecular-weight heparin was recently shown to be more effective than warfarin for cancer-related venous thromboembolism, its cost-effectiveness compared to traditional prophylaxis with warfarin is uncertain. We built a decision analytic model to evaluate the clinical and economic outcomes of a 6-month course of low-molecular-weight heparin or warfarin therapy in 65-year-old patients with cancer-related venous thromboembolism. We used probability estimates and utilities reported in the literature and published cost data. Using a US societal perspective, we compared strategies based on quality-adjusted life-years (QALYs) and lifetime costs. The incremental cost-effectiveness ratio of low-molecular-weight heparin compared with warfarin was 149,865 dollars/QALY. Low-molecular-weight heparin yielded a quality-adjusted life expectancy of 1.097 QALYs at the cost of 15,329 dollars. Overall, 46% (7108 dollars) of the total costs associated with low-molecular-weight heparin were attributable to pharmacy costs. Although the low-molecular-weigh heparin strategy achieved a higher incremental quality-adjusted life expectancy than the warfarin strategy (difference of 0.051 QALYs), this clinical benefit was offset by a substantial cost increment of 7,609 dollars. Cost-effectiveness results were sensitive to variation of the early mortality risks associated with low-molecular-weight heparin and warfarin and the pharmacy costs for low-molecular-weight heparin. Based on the best available evidence, secondary prophylaxis with low-molecular-weight heparin is more effective than warfarin for cancer-related venous thromboembolism. However, because of the substantial pharmacy costs of extended low-molecular-weight heparin prophylaxis in the US, this treatment is relatively expensive compared with warfarin.

Predicting recurrence after unprovoked venous thromboembolism: prospective validation of the updated Vienna Prediction Model.

The updated Vienna Prediction Model for estimating recurrence risk after an unprovoked venous thromboembolism (VTE) has been developed to identify individuals at low risk for VTE recurrence in whom anticoagulation (AC) therapy may be stopped after 3 months. We externally validated the accuracy of the model to predict recurrent VTE in a prospective multicenter cohort of 156 patients aged ≥65 years with acute symptomatic unprovoked VTE who had received 3 to 12 months of AC. Patients with a predicted 12-month risk within the lowest quartile based on the updated Vienna Prediction Model were classified as low risk. The risk of recurrent VTE did not differ between low- vs higher-risk patients at 12 months (13% vs 10%; P = .77) and 24 months (15% vs 17%; P = 1.0). The area under the receiver operating characteristic curve for predicting VTE recurrence was 0.39 (95% confidence interval [CI], 0.25-0.52) at 12 months and 0.43 (95% CI, 0.31-0.54) at 24 months. In conclusion, in elderly patients with unprovoked VTE who have stopped AC, the updated Vienna Prediction Model does not discriminate between patients who develop recurrent VTE and those who do not. This study was registered at www.clinicaltrials.gov as #NCT00973596.

Association between smoking and recurrence of venous thromboembolism and bleeding in elderly patients with past acute venous thromboembolism.

BACKGROUND: While the association between smoking and arterial cardiovascular events has been well established, the association between smoking and venous thromboembolism (VTE) remains controversial. OBJECTIVES: To assess the association between smoking and the risk of recurrent VTE and bleeding in patients who have experienced acute VTE. PATIENTS/METHODS: This study is part of a prospective Swiss multicenter cohort that included patients aged ≥65years with acute VTE. Three groups were defined according to smoking status: never, former and current smokers. The primary outcome was the time to a first symptomatic, objectively confirmed VTE recurrence. Secondary outcomes were the time to a first major and clinically relevant non-major bleeding. Associations between smoking status and outcomes were analysed using proportional hazard models for the subdistribution of a competing risk of death. RESULTS: Among 988 analysed patients, 509 (52%) had never smoked, 403 (41%) were former smokers, and 76 (8%) current smokers. After a median follow-up of 29.6months, we observed a VTE recurrence rate of 4.9 (95% confidence interval [CI] 3.7-6.4) per 100 patient-years for never smokers, 6.6 (95% CI 5.1-8.6) for former smokers, and 5.2 (95% CI 2.6-10.5) for current smokers. Compared to never smokers, we found no association between current smoking and VTE recurrence (adjusted sub-hazard ratio [SHR] 1.05, 95% CI 0.49-2.28), major bleeding (adjusted SHR 0.59, 95% CI 0.25-1.39), and clinically relevant non-major bleeding (adjusted SHR 1.21, 95% CI 0.73-2.02). CONCLUSIONS: In this multicentre prospective cohort study, we found no association between smoking status and VTE recurrence or bleeding in elderly patients with VTE.

Official warnings on thromboembolism risk with oral contraceptives fail to inform users adequately

Following the 1995 “pill scare” relating to the risk of venous thrombosis from taking second- or third-generation oral contraceptives, the Committee on Safety of Medicines (CSM) withdrew their earlier recommended restrictions on the use of third-generation pills and published recommended wording to be used in patient information leaflets. However, the effectiveness of this wording has not been tested. An empirical study (with 186 pill users, past users, and non-users) was conducted to assess understanding, based on this wording, of the absolute and relative risk of thrombosis in pill users and in pregnancy. The results showed that less than 12% of women in the (higher education) group fully understood the absolute levels of risk from taking the pill and from being pregnant. Relative risk was also poorly understood, with less than 40% of participants showing full understanding, and 20% showing no understanding. We recommend that the CSM revisit the wording currently provided to millions of women in the UK.