Incidental venous thromboembolism detected by PET-CT in patients with cancer: Prevalence and impact on survival rate

Introduction

People with cancer are at increased risk of incidental venous thromboembolism (VTE) and PET-CT imaging is commonly used in this population. However, the prevalence of incidental VTE detected by PET-CT in patients with cancer and its impact on survival are unknown.

Materials and Methods

This retrospective study was approved by the local Institutional Review Board. 1331 consecutive adult patients with cancer who underwent PET-CT examination between 2009 and 2012 were included in the study (mean age: 57 ± 15 years). PET-CT reports were reviewed to identify patients with incidental VTE at the time of examination. Survival rates were assessed with Kaplan-Meier curves. The Cox proportional hazards model was used to determine the association between incidental VTE and overall survival, after controlling for clinical variables.

Results

Incidental VTE was detected in 19 patients (1.4%). Patients with genitourinary malignancies, colorectal cancer and lung cancer had the highest rates of incidental VTE at PET-CT. At multivariate analysis, incidental VTE detected by PET-CT was associated with worse overall survival independently of patient age, hospitalization status at time of PET-CT examination, and the presence of metastatic disease (Hazard ratio = 2.03; 95% confidence interval = 1.08-3.81, p = 0.028).

Conclusion

Incidental VTE was detected in 1.4% of adult patients with cancer undergoing PET-CT imaging. Diagnosis of incidental VTE at PET-CT imaging was associated with worse overall survival in this population.     

Venous thromboembolism among United States soldiers deployed to Southwest Asia

INTRODUCTION: Military operations may represent a high-risk environment for venous thromboembolism (VTE). We sought to identify and describe cases of venous thromboembolism among US military personnel serving in Southwest Asia, and estimate relative disease rates compared to non-deployed personnel. MATERIALS AND METHODS: Retrospective review of imaging archives, hospital discharge codes, case logs and autopsy records for the diagnosis of deep vein thrombosis or pulmonary embolism occurring from 1 March 2003 through 29 February 2004 among U.S. military personnel deployed to Southwest Asia. Rates of disease in deployed and non-deployed active-duty soldiers were estimated using personnel data and deployment experience obtained from automated rosters. RESULTS: Forty cases of venous thromboembolism were identified. The case-fatality rate was 16% (3/19) among those with pulmonary embolism. Antecedent trauma followed by prolonged air evacuation was present in 55% (22/40). Compared to trauma-associated cases, non-trauma cases were more commonly over 40 years old (44% vs. 5%; p<0.05), assigned to a transportation or quartermaster company (56% vs. 14%; p<0.05), or had a history of remote venous thromboembolism (31% vs. 0%; p<0.05). The overall incidence among deployed active-duty soldiers was 22.1/100,000 person-years. Compared to non-deployed active-duty soldiers, the age-adjusted incidence rate ratio was 1.06 (CI(0.95) 0.68-1.67). CONCLUSIONS: VTE rates among deployed soldiers are relatively low compared to the general population, and are comparable to non-deployed soldiers. Fatalities from PE are not uncommon, and vigilance among clinicians remains warranted. Trauma followed by prolonged air evacuation or ground transport during military operations may represent unique interactive risk factors for venous thromboembolism.     

Health care expenditures associated with venous thromboembolism among children

Introduction

We used health insurance claims data from large samples of Medicaid-enrolled and privately insured children to identify children with venous thromboembolism (VTE) and to assess their use of health services and associated expenditures during 2009.

Materials and Methods

Data from the 2009 Thomson Reuters MarketScan® Commercial Database and Multi-State Medicaid database were used to estimate annual expenditures for children 1-17 years of age with VTE. Generalized linear models were used to calculate adjusted annual expenditures for Medicaid-enrolled and privately insured children with VTE, controlling for age, sex, type of health plan, VTE classification (deep vein thrombosis and/or pulmonary embolism), and type of VTE event (idiopathic or secondary) and race (Medicaid only) or region (Commercial only).

Results

During 2009, Medicaid-enrolled and privately insured children with VTE had an average of 1-2 inpatient admissions and 8-10 non-emergency department visits. Unadjusted mean total expenditures were similar for Medicaid-enrolled and privately insured children with VTE, $105,359 and $87,767, respectively. Adjusted mean expenditures for children with secondary VTE were five times higher than for children with idiopathic VTE.

Conclusions

Given the high frequency of secondary VTE in children, most of the associated expenditures may be due to other health conditions. However, children who develop a VTE incur substantial costs of care, even in the absence of related conditions. Additional research is needed to evaluate the long term outcomes for children with VTE including rates of readmission, complications, and the impact of co-morbid conditions.     

Old and new oral anticoagulants for venous thromboembolism and atrial fibrillation: a review of the literature

Heparin, fondaparinux and vitamin K antagonists (VKAs) are effective for the prevention and treatment of venous thromboembolism. VKAs reduce by almost 60% the rate of cardioembolic complications in patients with atrial fibrillation. The risk for bleeding and the inconvenience for laboratory monitoring, dose adjustment and drug or food interactions are the main limits for VKAs while parenteral administration is the main limit for heparin and fondaparinux. New oral anticoagulants with more predictable anticoagulant response and no need for laboratory monitoring have been shown to be effective for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The pharmacokinetic and pharmacodynamic profile of the new agents differ for mechanisms of action - mainly anti Xa and one antithrombin agent- bioavailability, half life, renal or live clearance. Drug interactions have been described with the new agents and inhibitors or inducers of P-gp or CYP3A4. Overall, in the prevention of venous thromboembolism after major elective orthopaedic surgery dabigatran was shown to be non-inferior, rivaroxaban and apixaban to be superior to enoxaparin. Both, rivaroxaban and dabigatran were shown to be non-inferior to low-molecular weight heparin and VKAs for the treatment of venous thromboembolism. Dabigatran 150 mg twice daily reduced the incidence of both ischemic and hemorrhagic stroke in patients with atrial fibrillation respect to warfarin. In these patients rivaroxaban and apixaban reduced the incidence of hemorrhagic stroke with a similar incidence of ischemic stroke. No bleeding concern emerged with the new anticoagulant agents in this indication.     

The MASTER registry on venous thromboembolism: description of the study cohort

INTRODUCTION: Information on the epidemiology and long-term clinical outcome of venous thromboembolism (VTE) is mainly based on data from clinical trials and thus may be not representative of the full spectrum of VTE patients. The aim of this multicenter registry (MASTER) was to prospectively collect data on the epidemiology and long-term clinical outcome of VTE in an unselected cohort of patients. MATERIALS AND METHODS: In symptomatic patients with objectively confirmed acute VTE, information about clinical presentation, diagnostic methods, temporary and permanent risk factors, pre-event prophylaxis and treatment were captured by an electronic data network at the time of the index event. A 24-month follow-up is currently ongoing. RESULTS: From January 2002 to October 2004, 2119 patients were included in the MASTER registry in 25 Italian centers. At entry, the mean patient age was 59.3+/-18.1 years (range 18-99 years). 1541 patients (72.7%) were affected by deep vein thrombosis, 206 patients (9.7%) by pulmonary embolism and 372 patients (17.5%) by both deep vein thrombosis and pulmonary embolism. 676 patients (31.9%) received home-treatment. 899 patients (42.4%) had one or more temporary risk factors. 381 patients (18.0%) had a known cancer at the time of the index event and in 50 patients (2.4%) a new cancer was discovered at the time of the index event. 311 patients (14.7%) had a previous VTE. CONCLUSIONS: Following a real world approach, our registry describes the clinical presentation, risk factors, diagnosis and treatment procedures in a large cohort of unselected patients with VTE.     

Fish intake and venous thromboembolism: A Danish follow-up study

Introduction

Data on the association between fish intake and venous thromboembolism (VTE) is sparse and inconsistent.

Objective

To investigate whether intake of total, lean or fatty fish is associated with development of incident VTE.

Material and methods

This study is based on the Danish follow-up study Diet, Cancer and Health including 27,178 men and 29,876 women aged 50–64 with no history of cancer. Participants were included between 1993 and 1997 and followed through 2006. Information on fish intake and potential confounders was obtained from baseline questionnaires. The outcome was incident VTE (all) and idiopathic VTE. We used Cox proportional hazard models with age as time axis. Separate analyses were performed for men and women. Adjustment was made for BMI, smoking, physical activity, energy intake and women’s use of hormone replacement therapy.

Results

During follow-up, 641 incident VTE events were verified. We found no association between total fish intake and VTE, but moderate intake of fatty fish was associated with a statistically non-significant 20-40% lower risk of idiopathic VTE compared with consumption of a low intake (less than 8 g) of fatty fish per day.

Conclusions

Intake of neither total nor fatty fish was statistically significantly associated with the incidence rate of VTE. However, intake of fatty fish may be associated with a reduction of the risk of idiopathic VTE.     

Incidental venous thromboembolism in cancer patients: prevalence and consequence

Introduction

Careful re-evaluation of CT-scans for cancer staging frequently reveals unsuspected venous thromboembolism (VTE) on CT-scans. However, it is unknown how often these findings lead to anticoagulant treatment in daily clinical practice.

Methods

Reports from thoracic and/or abdominal CT-scans performed in a consecutive series of patients to stage cancer were retrospectively evaluated to determine the prevalence of incidental venous thromboembolism (iVTE). Presence of pre-existing signs of VTE, anticoagulant treatment and 3-month follow-up were analysed in patients with iVTE.

Results

A total of 1466 staging scans (838 patients) from the year 2006 were included in the analysis. The prevalence of VTE in patients was 2.5% (21/838 patients, 95% confidence interval 1.6-3.8%); the prevalence of VTE on scans was 1.4% (21/1466 scans, 95% CI 0.9-2.2%). Incidental PE or deep vein thrombosis (DVT) was observed in 11 (1.3%, 0.7-2.3%) and abdominal vein thrombosis in 9 patients (1.1%, 0.6-2.0%; in the portal (5), mesenteric (3) and renal vein (1), respectively). Nine out of eleven patients with PE/DVT were treated with anticoagulants, while none of the patients with thrombosis in other locations received anticoagulants. One of these patients developed symptomatic PE one month later; otherwise, follow up was uneventful in the untreated patients.

Conclusion

The prevalence of iVTE in patients with cancer in clinical practice is relatively low and most patients with PE or DVT are treated with anticoagulants. For patients with thrombi in other locations, further research is necessary to understand the natural history of these thrombi in order to develop adequate guidelines.     

Risk factors for venous thromboembolism in pre-and postmenopausal women

Introduction

Hemostasis in women is affected by changes of estrogen levels. The role of endogenous estrogens on risk of venous thromboembolism (VTE) remains unclear. The aim of this study was to investigate the importance of acquired and genetic risk factors for VTE in pre-and postmenopausal women.

Method

In a nationwide case-control study we included as cases 1470 women, 18 to 64 years of age with a first time VTE. The 1590 controls were randomly selected and matched by age to the cases. Information on risk factors was obtained by interviews and DNA-analyses. We used unconditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs).

Results

The ORs were generally of similar magnitude in pre- and postmenopausal women. The highest risk was for the combination of surgery and cast (adjusted OR 54.12, 95% CI 16.62-176.19) in postmenopausal women. The adjusted OR for use of menopausal hormone therapy was 3.73 (95% CI 1.86-7.50) in premenopausal and 2.22 (95% CI 1.54-3.19) in postmenopausal women. Overweight was linked to an increased risk and exercise to a decreased risk, regardless of menopausal status.

Conclusion

Menopausal status had only minor influence on the risk levels. Acquired transient risk factors conveyed the highest risks for VTE.     

Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and risk of venous thromboembolism: A meta-analysis

Introduction

The plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism was considered to be associated with risk of venous thromboembolism (VTE), while evidence remains inadequate. To provide a more accurate estimation of this relationship, we performed an updated meta-analysis of all eligible studies.

Materials and Methods

A systematical search was performed in PubMed, EMBASE, Wanfang, China National Knowledge Infrastructure (CNKI) and Cqvip databases to identify relevant studies published before March 6^th 2014. The odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using the fixed/random-effects model using Review Manager 5.1 and STATA 12.0.

Results

A total of 34 studies with 3561 cases and 5693 controls were analyzed. Overall, significant association between the PAI-1 4G/5G variant and VTE risk in total population (dominant model: OR = 1.32, 95%CI: 1.13-1.54) was observed. And this variant was also related to the deep vein thrombosis risk (dominant model: OR = 1.60, 95%CI: 1.24-2.06, P = 0.0003). In the subgroup analyses on ethnicity, significant results were obtained in both Asians (dominant model: OR = 2.08, 95%CI: 1.29-3.35, P = 0.003) and Caucasians (dominant model: OR = 1.31, 95%CI: 1.10-1.56, P = 0.003). However, no significant association was found in patients with provoked VTE. In terms of subgroup analyses on co-existence of other thrombotic risk factors, the PAI-1 4G/5G polymorphism was significantly associated with VTE risk in patients with factor V Leiden mutation (dominant model: OR = 1.72, 95%CI: 1.17-2.53), but not in patients with cancer or surgery.

Conclusion

Our findings demonstrate the role of PAI-1 4G/5G polymorphism being a risk candidate locus for VTE susceptibility, especially in patients with other genetic thrombophilic disorders.     

Predictive blood coagulation markers for early diagnosis of venous thromboembolism after total knee joint replacement

Pulmonary embolism development may be prevented if asymptomatic venous thromboembolism (VTE) can be predicted and treated preoperatively or soon after total knee arthroplasty (TKA). The purpose of this study was to evaluate whether asymptomatic VTE can be predicted by blood coagulation markers preoperatively or early after TKA. This prospective single-centre study enrolled 68 patients (6 men, 62 women; mean age: 71 years) who underwent TKA between September 2004 and August 2009. Sixteen-row multidetector computed tomography was performed 4 days before and after surgery for diagnosis of asymptomatic VTE. Blood samples were taken to measure the plasma levels of soluble fibrin monomer complex (SFMC), D-dimer and cross-linked fibrin degradation products by leukocyte elastase (e-XDP) at 4 days preoperatively, and at 1 hour, 1 day and 4 days postoperatively. The preoperative SFMC, D-dimer and e-XDP levels did not differ significantly between the thrombus (n = 36) and no-thrombus (n = 32) groups. D-dimer and e-XDP levels showed the most significant increases at days 4 and 1, respectively, after surgery in the thrombus group. With cut-off points of 7.5 μg/ml for D-dimer and 8.2 U/ml for e-XDP, the sensitivities were 75% and 75%, and the specificities were 63% and 59%, respectively. By multiple logistic regression analysis, D-dimer at day 4 and e-XDP at day 1 postoperatively were independent markers for early diagnosis of VTE (odds ratio = 1.61 and 1.19, P = 0.01 and 0.04, respectively). The postoperative occurrence of new asymptomatic VTE may be predicted by D-dimer at day 4 and e-XDP at day 1 after TKA.     

The association of alpha-fibrinogen Thr312Ala polymorphism and venous thromboembolism in the LITE study

INTRODUCTION: The alpha-fibrinogen Thr312Ala variant has been shown to influence clot structure through increased factor XIII cross-linking and formation of thicker fibrin fibers. However, the effect of this common variant on risk of venous thromboembolism (VTE) is unclear. This paper reports the association between the Thr312Ala variant and VTE in the LITE study. MATERIALS AND METHODS: 506 cases and 1014 controls frequency matched on age, sex, race, and study were drawn from two prospective studies and included in the analysis. Logistic regression was used to examine the association between Thr312Ala and VTE. RESULTS: In a logistic regression model minimally adjusted for the matching variables, the Thr312Ala TA and AA genotypes were associated with a significantly higher risk of VTE than the TT genotype (TA OR and 95% confidence interval 1.27 [1.01-1.60], AA OR 1.49 [1.00-2.22]). Associations were similar in analyses of PE and DVT considered separately and across racial and study subgroups. The association between alpha-fibrinogen Thr312Ala and VTE was modified by both BMI and the FXIII Val34Leu variant; the combination of elevated BMI or FXIII Val34Leu with alpha-fibrinogen Thr312Ala conveyed lower odds of VTE than would be expected by an additive or multiplicative model of individual risk factors. CONCLUSIONS: These results suggest that alpha-fibrinogen Thr312Ala is involved in the pathogenesis of VTE and that its action may be modified by other VTE risk factors.     

Red cell distribution width and risk for venous thromboembolism: A population-based cohort study

Introduction

Red cell distribution width (RDW) has been associated with venous thromboembolism (VTE), but whether RDW is a predictor of first event of VTE is unknown. We investigated the association between RDW and incidence of first event of VTE in a population-based cohort.

Materials and Methods

RDW was measured in 27 042 subjects (aged 45–73 years, 60.6% women), without previous history of VTE or cancer within 5 years before follow-up, who participated in the Malmö Diet and Cancer study during 1991–1996. Incidence of VTE was identified from the patient register and the cause of death register during a mean follow-up of 13.8 years and studied in relation to RDW.

Results

During follow-up, 991 subjects (57.5% women) were affected by VTE (pulmonary embolism or deep venous thrombosis of the lower limbs). After adjustment for potential confounding factors the hazard ratios (HR) for VTE for the second, third and fourth RDW quartiles 1.15 (95% confidence interval 0.94–1.41), 1.41 (1.14–1.73), 1.74 (1.38–2.21), respectively, were compared with the bottom quartile of RDW. In the multivariate model subjects with the top 5% of RDW values compared with the bottom quartile had an even higher risk (HR = 2.51, 1.78–2.54). In receiver operating characteristic (ROC) analysis, the male specific area under the ROC curve (AUC) for RDW was 0.57 (95% CI 0.54–0.59). The female specific AUC was 0.56 (95% CI 0.53–0.58).

Conclusions

RDW was found to be associated with long-term incidence of first event of VTE among middle-aged subjects.     

Predictors of attempted inferior vena cava filters retrieval in a tertiary care centre

Background

Retrieval rates of optional recovery inferior vena cava (IVC) filters in US hospitals range from 11 - 70%. We conducted a retrospective study in a Canadian tertiary care centre to determine retrieval rates and predictors of filter removal.

Methods

Consecutive patients who had a retrievable IVC filter inserted or removed between January 2007 and December 2010 were identified. Data collected included baseline demographics, indications for filter insertion and removal, documentation of an IVC filter management plan, reasons for non-retrieval, complications, and death.

Results

275 patients with a median age of 60 years were followed in hospital for a median of 17 patient-days (range 1–876). Indications for filter placement were acute or prior VTE with contraindication to anticoagulation (72.4%), high risk of PE (11.3%) and primary prophylaxis (13.8%). Retrieval was attempted in 165 patients (60%) and was successful in 146 patients (53.1%). The most common reason for failed retrieval was filter thrombus. Predictors of attempted retrieval included documentation of filter plan (odds ratio [OR] 16.7; p < 0.001), surgical indication for IVC filter insertion (OR 4.8; p = 0.002), age ≤ 70 years (OR 3.8; p = 0.001), Hematology service involvement (OR 3.0; p = 0.006), and presence of metastatic cancer (OR 0.2; p = 0.001). Thrombotic complications occurred in 48 patients, including 3 patients who died of fatal PE.

Conclusion

Our filter retrieval rate is suboptimal. Improvements in follow-up documentation or a dedicated clinical service may help increase retrieval rates.     

Feasibility of an easy-to-use risk score in the prevention of venous thromboembolism and placental vascular complications in pregnant women: a prospective cohort of 2736 women

INTRODUCTION: Management of pregnant women at increased risk of venous thromboembolism (VTE) remains complex in the absence of an easy-to-use tool allowing individualised, risk-adapted prophylaxis. Our objective was to assess whether treatment based on risk score is feasible in these women. MATERIALS AND METHODS: A scoring system for VTE risk in pregnant women was developed, each score being associated with a specific treatment. This system was implemented in a prospective cohort of 2736 consecutive women delivered in our teaching hospital from July 2002 to June 2003. Thromboembolic and obstetrical outcomes during pregnancy and the early post-partum period were recorded. RESULTS: Treatment based on risk score was implemented in 2685 of the 2736 women included (98.1%). The scoring system identified 2431 women with no risk factor and 305 women (11%) with at least one risk factor. Eight women not at risk (0.3%, [95% CI: 0.1-0.5]) and one at risk (0.4%, [95% CI: 0-1.1]) experienced a VTE. This low event rate precluded estimation of the discriminatory power of the score. However, the benefit of the scoring system was evaluated indirectly by assessing VTE incidence in the 46 women at risk in whom it was not used (15.2%, [95% CI: 4.8-25.6]). CONCLUSIONS: Our simple scoring system offers an easily implemented procedure for risk-based VTE prophylaxis of pregnant women and the proposed therapeutic strategy appears to be effective and safe in reducing VTE. The discriminatory power of the score is currently being evaluated in a randomized, controlled trial.     

Contribution of multiple thrombophilic and transient risk factors in the development of cerebral venous thrombosis

INTRODUCTION: Cerebral venous thrombosis (CVT), deep vein thrombosis (DVT) and/or pulmonary embolism (PE) have been associated with thrombophilic defects. However, in contrast to DVT or PE, CVT is a rare disease. We performed a study to identify differences in thrombotic risk profile, predisposing to CVT rather than DVT or PE, particularly the contribution of oral contraception and 11 thrombophilic defects. MATERIALS AND METHODS: A single center case-control study (63 CVT cases and 209 controls with DVT or PE) was performed. RESULTS: Of CVT patients, 11% had experienced prior DVT or PE, and none had recurrent CVT at 5 years follow-up. CVT was more frequently observed in females (79% versus 51%, P<0.001). It was more often secondary (75% versus 50%, P<0.001), mainly due to the difference in age between both groups. At presentation of CVT and DVT/PE, oral contraceptives were used by 78% and 74% of non-pregnant fertile women (P=0.8), respectively. Any thrombophilic defect was demonstrated in 88% of CVT and 75% of DVT/PE patients (P=0.22), sex and age matched. Individual and two or more defects were equally distributed among both groups. CONCLUSIONS: We conclude that a majority of CVT and DVT or PE patients show single or multiple thrombophilic defects. At presentation, oral contraceptive intake was observed more frequently in CVT patients. However, no differences were observed in thrombotic risk profile between both groups of comparable age. Hence, additional unknown risk factors should be considered to explain the different sites of thrombosis in these patients.     

Sensitive and quantitative, 10-min immunofluorometric assay for D-Dimer in whole blood

INTRODUCTION: Normal concentrations of D-Dimer can be used to exclude venous thromboembolism (VTE). However, methods for sensitive and quantitative D-Dimer measurements at the point-of-care (POC) are still limited. MATERIALS AND METHODS: We developed a 10-min, non-competitive immunofluorometric assay for D-Dimer in citrated whole blood and plasma using pre-dispensed reagents dried in single assay wells. The simple, automated assay procedure comprises a 1:50 sample dilution, one-step incubation, washing, and time-resolved fluorometric measurement directly from the wet well surface. RESULTS: The limits of detection (background + 3SD) and quantification (CV <15%) were 0.05 and 0.2 mg/L D-Dimer, respectively, and the assay was linear up to 400 mg/L. Correlations to Roche TinaQuant (r=0.726, n=200) and Biopool Auto.Dimer (r=0.190, n=149) were carried out using citrated plasma. Diagnostic sensitivity, specificity, and negative (NPV) and positive (PPV) predictive values were 98.7%, 64.4%, 99.1% and 55.1%, and 92.2%, 81.0%, 95.9% and 68.3%, respectively, using cut-off values of 0.6 and 1.0 mg/L, respectively, in outpatients with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) (n=77) compared with outpatients with various other diseases (n=174). The within- and between-run CVs near the cut-off values were < or =10% in both whole blood and plasma. The 95th percentile upper range in apparently healthy individuals was 0.68 mg/L of whole blood (n=101). CONCLUSIONS: The high sensitivity and NPV suggest that the rapid immunofluorometric assay could be valuable for rapid exclusion of VTE in outpatients. With appropriate cut-offs, the assay could potentially be used as a stand-alone test or combined with clinical probability assessment, but further studies are required.     

Clustering of venous thrombosis events at the start of tamoxifen therapy in breast cancer: a population-based experience

Introduction

The epidemiology of tamoxifen and venous thromboembolism (VTE) is not well understood, and most data on tamoxifen toxicity are from adjuvant clinical trials. This study examined the relationship between the duration of tamoxifen use in female patients with breast cancer and the risk of VTE in a large population-based setting.

Materials and Methods

Retrospective electronic data extraction on tamoxifen utilization was undertaken among a cohort of 3572 women with breast cancer seen at Marshfield Clinic between January 1, 1994 and June 31, 2009. Observational follow-up extended until February, 2010.

Results

On initial exposure to tamoxifen, women had a clustering of VTE events. Cox proportional hazards regression, adjusting for multiple clinically-important covariates including age, body mass index, cancer stage, and concurrent diabetes, demonstrated that as use of tamoxifen continued in those without earlier VTE events, risk of subsequent VTE gradually increased, albeit at a lower rate (hazard ratio per year of tamoxifen duration = 1.225, P < 0.0001).

Conclusions

In our study population, initiating tamoxifen coincided with an initial clustering of VTE events, with risks due specifically to tamoxifen, increasing during continued exposure. Evidence suggested that the VTE clustering occurred in high risk individuals at initiation of tamoxifen therapy. Careful selection of patients for whom tamoxifen therapy is appropriate based on susceptibility to VTE is thus required prior to initiation of therapy.     

Statins in the prevention of venous thromboembolism: a meta-analysis of observational studies

Introduction

Studies have established a relationship between inflammation and venous thromboembolism (VTE). Though statins modulate inflammation, it is uncertain if they prevent VTE in heterogeneous populations. A recent randomized trial demonstrated that statins prevent VTE in healthy older adults, yet this has not been well established in other groups, including younger individuals and individuals with comorbidities. The objective of this meta-analysis was to estimate the effect of statins on VTE in a heterogeneous group of adults.

Methods

We systematically reviewed the effect of statins in preventing VTE in adult inpatients and outpatients. We systematically searched MEDLINE (1966-Jan 2010), EMBASE (1980-Jan 2010), Google Scholar, Cochrane Library, PapersFirst, ProceedingsFirst, and ISI Web of Science, manually reviewed references, and contacted experts. Observational studies that compared any dose of statin to no statin or placebo, examined inpatients or outpatients, and assessed VTE, pulmonary embolism, and/or deep vein thrombosis were included. Study selection, data abstraction and study quality evaluation (using the Newcastle-Ottawa Scale) were independently conducted in duplicate.

Results

Four cohort studies and four case-control studies met criteria. Comparing statins to control, the odds ratio for VTE was 0.67 (95% confidence interval 0.53, 0.84), and for deep vein thrombosis was 0.53 (95% confidence interval 0.22, 1.29). The association was attenuated in lower-quality studies and studies enrolling older individuals.

Conclusions

Further well-designed trials are needed to evaluate the risks and benefits of statins in preventing VTE in heterogenous populations of adults, identify high-risk subgroups, and analyze cost-effectiveness of statin use for this indication.     

FGB mutations leading to congenital quantitative fibrinogen deficiencies: An update and report of four novel mutations

Introduction

Causative mutations leading to congenital quantitative fibrinogen are frequently clustered in FGA encoding the fibrinogen Aα-chain. Mutations of FGB encoding the Bβ-chain are less common and of interest since the Bβ-chain is considered the rate-limiting factor in the hepatic production of the fibrinogen hexamer.

Method

Four novel FGB mutations were identified in two afibrinogenemic (one new-born and one 30 years old male) and hypofibrinogenemic (a 49 years old female) patient, with heterogeneous thrombotic and bleeding phenotype. The human fibrinogen beta chain precursor protein sequence (P02675) was obtained from the UniProt database. The resulting models were analysed in SwissPdbViewer 4.1 and POV-Ray 3.7.

Results

The FGB c.895 T>C p.Y299H (numbering from the initiator Met) and the FGB c.1415G>T p.G472V were predicted to be deleterious by SIFT analysis. The first replaces an uncharged aromatic amino acid side chain by a positively charged side chain modifying the balance in the distribution of hydrophobic and hydrophilic of the 10 Å neighbourhood residues. The second replaces one non-charged aliphatic side chain by another without any changes for the 10 Å surrounding region. The FGB c.352C>T p.Q118X leads to a severe premature termination codon and the FGB intron 4: IVS4-1G>C (c719-1G>C) leads to skipping of exon 5 or usage of a cryptic acceptor site located upstream or downstream of the normal site.

Conclusions

The continuous characterization of novel molecular defects responsible for fibrinogen deficiency combined with modelling of mutant proteins will continue to provide a better comprehension of the complexity of fibrinogen synthesis and physiology.