Monocyte recruitment in venous pulmonary embolism at time of cancer diagnosis in upper gastrointestinal cancer patients.

Upper gastrointestinal cancer is frequently complicated by venous thromboembolisms (VTE), especially pulmonary embolisms (PE) increase the mortality rate. Monocytes are a part of the innate immune system and up-regulation may indicate an ongoing inflammatory response or infectious disease and has lately been associated with a moderate risk of suffering from VTE. This prospectively study aims to compare the incidence of pulmonary embolism with markers of coagulation and compare it to the absolute monocyte count. A consecutive cohort of 250 patients with biopsy proven upper gastrointestinal cancer (i.e. pancreas, biliary tract, esophagus and gastric cancer) where included at the time of cancer diagnosis and before treatment. All patients underwent bilateral compression ultrasonography for detection of deep vein thrombosis (DVT). Of these 143 had an additionally pulmonary angiografi (CTPA) with the staging computer tomography. 13 of 250 patients (5.2%) had a DVT and 11 of 143 (7.7%) had CTPA proven PE. PE was significantly more common among patients with elevated D-dimer (OR 11.62, 95%CI: 1.13-119, P = 0.039) and elevated absolute monocyte count (OR 7.59, 95%CI: 1.37-41.98, P = 0.020). Only patients with pancreatic cancer had a significantly higher risk of DVT (OR 11.03, 95%CI: 1.25-97.43, P = 0.031). The sensitivity of absolute monocyte count was 63.6 (95%CI: 30.8-89.1) and specificity 80.3 (95%CI: 72.5-86.7), with a negative predictive value of 96.4 (95%CI: 91-99) in PE. An increased absolute monocyte count was detected in patients suffering from PE but not DVT, suggesting a possible interaction with the innate immune system.

How are pay-for-performance schemes in healthcare designed in low- and middle-income countries? Typology and systematic literature review.

BACKGROUND: Pay for performance (P4P) schemes provide financial incentives to health workers or facilities based on the achievement of pre-specified performance targets and have been widely implemented in health systems across low and middle-income countries (LMICs). The growing evidence base on P4P highlights that (i) there is substantial variation in the effect of P4P schemes on outcomes and (ii) there appears to be heterogeneity in incentive design. Even though scheme design is likely a key determinant of scheme effectiveness, we currently lack systematic evidence on how P4P schemes are designed in LMICs. METHODS: We develop a typology to classify the design of P4P schemes in LMICs, which highlights different design features that are a priori likely to affect the behaviour of incentivised actors. We then use results from a systematic literature review to classify and describe the design of P4P schemes that have been evaluated in LMICs. To capture academic publications, Medline, Embase, and EconLit databases were searched. To include relevant grey literature, Google Scholar, Emerald Insight, and websites of the World Bank, WHO, Cordaid, Norad, DfID, USAID and PEPFAR were searched. RESULTS: We identify 41 different P4P schemes implemented in 29 LMICs. We find that there is substantial heterogeneity in the design of P4P schemes in LMICs and pinpoint precisely how scheme design varies across settings. Our results also highlight that incentive design is not adequately being reported on in the literature - with many studies failing to report key design features. CONCLUSIONS: We encourage authors to make a greater effort to report information on P4P scheme design in the future and suggest using the typology laid out in this paper as a starting point.

MicroRNAs and Neutrophil Activation Markers Predict Venous Thrombosis in Pancreatic Ductal Adenocarcinoma and Distal Extrahepatic Cholangiocarcinoma.

Cancer-associated venous thrombosis (VTE) increases mortality and morbidity. However, limited tools are available to identify high risk patients. Upon activation, neutrophils release their content through different mechanisms, thereby prompting thrombosis. We explored plasma microRNAs (miRNAs) and neutrophil activation markers to predict VTE in pancreatic ductal adenocarcinoma (PDAC) and distal extrahepatic cholangiocarcinoma (DECC). Twenty-six PDAC and 6 DECC patients recruited at cancer diagnosis, were examined for deep vein thrombosis and pulmonary embolisms, and were then followed-up with clinical examinations, blood collections, and biCUS. Ten patients developed VTE and were compared with 22 age- and sex-matched controls. miRNA expression levels were measured at diagnosis and right before VTE, and neutrophil activation markers (cell-free DNA, nucleosomes, calprotectin, and myeloperoxidase) were measured in every sample obtained during follow-up. We obtained a profile of 7 miRNAs able to estimate the risk of future VTE at diagnosis (AUC = 0.95; 95% Confidence Interval (CI) (0.987, 1)) with targets involved in the pancreatic cancer and complement and coagulation cascades pathways. Seven miRNAs were up- or down-regulated before VTE compared with diagnosis. We obtained a predictive model of VTE with calprotectin as predictor (AUC = 0.77; 95% CI (0.57, 0.95)). This is the first study that addresses the ability of plasma miRNAs and neutrophil activation markers to predict VTE in PDAC and DECC.

Real-Time Interferometric Refractive Index Change Measurement for the Direct Detection of Enzymatic Reactions and the Determination of Enzyme Kinetics.

Back scatter interferometry (BSI) is a sensitive method for detecting changes in the bulk refractive index of a solution in a microfluidic system. Here we demonstrate that BSI can be used to directly detect enzymatic reactions and, for the first time, derive kinetic parameters. While many methods in biomedical assays rely on detectable biproducts to produce a signal, direct detection is possible if the substrate or the product exert distinct differences in their specific refractive index so that the total refractive index changes during the enzymatic reaction. In this study, both the conversion of glucose to glucose-6-phosphate, catalyzed by hexokinase, and the conversion of adenosine-triphosphate to adenosine di-phosphate and mono-phosphate, catalyzed by apyrase, were monitored by BSI. When adding hexokinase to glucose solutions containing adenosine-triphosphate, the conversion can be directly followed by BSI, which shows the increasing refractive index and a final plateau corresponding to the particular concentration. From the initial reaction velocities, KM was found to be 0.33 mM using Michaelis⁻Menten kinetics. The experiments with apyrase indicate that the refractive index also depends on the presence of various ions that must be taken into account when using this technique. This study clearly demonstrates that measuring changes in the refractive index can be used for the direct determination of substrate concentrations and enzyme kinetics.

Analytical and between-subject variation of thrombin generation measured by calibrated automated thrombography on plasma samples.

BACKGROUND: The Calibrated Automated Thrombography (CAT) is an in vitro thrombin generation (TG) assay that holds promise as a valuable tool within clinical diagnostics. However, the technique has a considerable analytical variation, and we therefore, investigated the analytical and between-subject variation of CAT systematically. Moreover, we assess the application of an internal standard for normalization to diminish variation. METHODS: 20 healthy volunteers donated one blood sample which was subsequently centrifuged, aliquoted and stored at -80 °C prior to analysis. The analytical variation was determined on eight runs, where plasma from the same seven volunteers was processed in triplicates, and for the between-subject variation, TG analysis was performed on plasma from all 20 volunteers. The trigger reagents used for the TG assays included both PPP reagent containing 5 pM tissue factor (TF) and PPPlow with 1 pM TF. Plasma, drawn from a single donor, was applied to all plates as an internal standard for each TG analysis, which subsequently was used for normalization. RESULTS: The total analytical variation for TG analysis performed with PPPlow reagent is 3-14% and 9-13% for PPP reagent. This variation can be minimally reduced by using an internal standard but mainly for ETP (endogenous thrombin potential). The between-subject variation is higher when using PPPlow than PPP and this variation is considerable higher than the analytical variation. CONCLUSION: TG has a rather high inherent analytical variation but considerable lower than the between-subject variation when using PPPlow as reagent.

Impact of incident venous thromboembolism on risk of arterial thrombotic diseases.

BACKGROUND: Growing evidence supports an association between venous thromboembolism (VTE) and arterial thrombotic diseases (ie, myocardial infarction and ischemic stroke). We aimed to study the association between VTE and future arterial events and to determine the population attributable risk of arterial events by VTE in a large prospective cohort recruited from the general population. METHODS AND RESULTS: In 1994 to 1995 and 1993 to 1997, 81 687 subjects were included in the Tromsø Study and in the Diet, Cancer and Health Study and followed up to the date of incident venous and arterial events (myocardial infarction or ischemic stroke), death or migration, or to the end of the study period (2010 and 2008, respectively). There were 1208 cases of VTE and 90 subsequent arterial events during a median follow-up of 12.2 years. An association between VTE and future arterial events was found in all women and men aged <65 years but not in men aged >65 years. Women <65 years old with VTE had 3.3-fold higher risk of arterial disease (adjusted hazard ratio, 3.28; 95% confidence interval, 1.69-6.35) compared with women of the same age without VTE. The corresponding hazard ratio in men aged <65 years was 2.06 (95% confidence interval, 1.32-3.20). Only 0.9% of the arterial events were attributed to VTE, and the VTE explained 63.8% of the risk of arterial events among VTE patients. CONCLUSIONS: Our findings imply that women and young men with VTE have higher risk of arterial thrombotic disease than those without VTE. However, only 1% of the arterial thrombotic events in the population are attributed to VTE.

Are Gamers Prone to eThrombosis during Long Gaming Sessions?

During the last two decades, several cases of venous thrombosis (VTE) after a prolonged period at a computer have been described, denominated as "eThrombosis". Video gaming on a computer has become very popular and can be a social activity where several players gather to play against each other or in a virtual environment for several days ("LAN (i.e., Local Area Network) parties") where the participants are sedentary and consuming calorie-rich food items. The aim of this study was to investigate potential coagulation activation during a 42 h LAN party. Nine male gamers volunteered for the LAN party. Citrated blood was sampled before and every 6 h, and plasma was analyzed for thrombin generation, thrombin-antithrombin complexes (TAT), prothrombin fragment 1 + 2 (F1 + 2), and D-dimer. Thrombin generation increased slightly but not significantly during the LAN party, whereas the coagulation activation markers were unchanged. These results do not indicate that the coagulation system is activated significantly during 42 h of gaming with minimal physical activity. Although increased activity cannot be excluded, it does not directly indicate a risk of VTE in general.

Single nucleotide polymorphisms and the risk of venous thrombosis: results from a Danish case-cohort study.

A number of single nucleotide polymorphisms (SNP) have been linked to higher risk of venous thromboembolism (VTE). We investigated the VTE risk associated with SNPs in the GP6 (rs1613662), SERPINC1 (rs2227589), F11 (rs2036914 and rs2289252), FGG (rs2066865), and F12 (rs1801020) genes. In F11, the CC genotype for rs2036914 and the CT and TT genotypes for rs2289252 were associated with a significantly higher VTE risk. A trend toward a thrombogenic effect was observed for the risk alleles of the GP6 and FGG SNPs. Risk estimates were unaffected by adjustments for blood type and F5 rs6025 (Factor V Leiden) mutation.

Survival after cancer-related venous thrombosis: the Scandinavian Thrombosis and Cancer Study.

Patients with cancer have an increased risk of developing venous thromboembolism (VTE), and this combination is reported to result in poorer survival compared with cancer alone. This study aimed to investigate the impact of VTE on the survival of patients with cancer in a general population. The Scandinavian Thrombosis and Cancer (STAC) cohort, a population-based cohort including 144 952 participants without previous VTE or cancer, was used. During follow-up, cancer and VTE incidences were registered. "Cancer-related VTE" was defined as VTE diagnosed in patients with overt or occult cancer. The survival of participants without cancer and/or VTE ("disease-free") was compared with the survival of participants with cancer and cancer-related VTE. Cox regression models with cancer and VTE as time-varying exposures were performed to calculate hazard ratios for death. Subanalyses were performed across cancer types and stages and VTE type (deep vein thrombosis or pulmonary embolism). During follow-up (mean, 11.7 years), 14 621 participants developed cancer, and 2444 developed VTE, of which 1241 were cancer-related. The mortality rates (per 100 person years) for disease-free participants, VTE only, cancer only, and cancer-related VTE were 0.63, 5.0, 9.2, and 45.3, respectively. Compared with patients with cancer only, the risk of death for patients with cancer-related VTE was increased 3.4-fold. Within all cancer types, the occurrence of VTE increased the mortality risk 2.8- to 14.7-fold. In a general population, patients with cancer with VTE had a 3.4-fold higher mortality risk than patients with cancer without VTE, independent of cancer type.

Calculating acid-base and oxygenation status during COPD exacerbation using mathematically arterialised venous blood.

BACKGROUND: Repeated arterial puncture is painful. A mathematical method exists for transforming peripheral venous pH, PCO 2 and PO 2 to arterial eliminating the need for arterial sampling. This study evaluates this method to monitor acid base and oxygenation during admission for exacerbation of chronic obstructive pulmonary disease (COPD). METHODS: Simultaneous arterial and peripheral venous blood was analysed. Venous values were used to calculate arterial pH, PCO 2 and PO 2, with these compared to measured values using Bland-Altman analysis and scatter plots. Calculated values of PO 2 were assessed with previously defi ned rules.Differences between maximal changes of calculated and measured values were compared using a t-test, with trends analysed by inspection of plots. RESULTS: Fifty-four patients, median age 67 years (range 62 ­ 75), were studied on average 3 days. Mean values of pH,PCO 2 and PO 2 were 7.432 } 0.047, 6.8 } 1.7 kPa and 9.2 } 1.5kPa, respectively. Calculated and measured arterial pH and PCO 2 agreed well, differences having small bias and SD(0.000 } 0.022 pH, ­ 0.06 } 0.50 kPa PCO 2 ), significantly better than venous blood alone. Calculated PO 2 obeyed the clinical rules. Calculated values could track patients, with no significant differences in maximal changes in measured and calculated values (pH p = 0.96, PCO 2 p = 0.62, PO 2 p = 0.33), and time-course plots matching quantity and pattern of change in measurements. CONCLUSIONS: This study shows that arterial pH, PCO 2 and PO 2 can be calculated from peripheral venous values so as to characterise changes seen during exacerbation. Application of the method has potential to reduce arterial sampling, decrease discomfort and enable venous sampling as routine practice.

Atrial fibrillation, liver cirrhosis, thrombosis, and bleeding: A Danish population-based cohort study.

OBJECTIVES: We examined the impact of liver cirrhosis on the risk of thromboembolic events and bleeding complications in patients with atrial fibrillation or flutter (AFF). METHODS: This population-based cohort study used data from Danish health registries. We identified all patients with a first-time diagnosis of AFF during 1995 to 2015, and followed them from their AFF diagnosis until the end of 2016. Patients were categorized according to the presence or absence of liver cirrhosis. We computed incidence rates per 1000 person-years and hazard ratios (HRs) with 95% confidence intervals (CIs) based on Cox regression analyses, adjusting for age, CHA2DS2VASc score, and Charlson Comorbidity Index score. RESULTS: We identified 273 225 patients with AFF. Of these, 1463 (0.54%) had liver cirrhosis. During 0 to 5 years of follow-up, compared to patients without liver cirrhosis, patients with liver cirrhosis had higher incidence rates and hazards of ischemic stroke (29.7 vs 21.6; HR, 1.3; 95% CI, 1.1-1.6), venous thromboembolism (9.2 vs 5.5; HR, 1.5; 95% CI, 1.2-2.3), but not myocardial infarction (10.2 vs 11.2; HR, 0.9; 95% CI, 0.7-1.2). Patients with liver cirrhosis also had higher rates of hemorrhagic stroke (5.8 vs 3.3; HR, 1.7; 95% CI, 1.1-2.6), subdural hemorrhage (5.3 vs 1.6; HR, 3.2; 95% CI, 2.1-4.9), hemorrhage of the lung or urinary tract (24.6 vs 15.2; HR, 1.6; 95% CI, 1.3-2.0), and gastrointestinal hemorrhage (34.5 vs 10.4; HR, 3.3; 95% CI, 2.7-3.9). CONCLUSION: In patients with AFF, liver cirrhosis was associated with an elevated risk of ischemic stroke, venous thromboembolism, and all evaluated bleeding complications.

Who is paid in pay-for-performance? Inequalities in the distribution of financial bonuses amongst health centres in Zimbabwe.

Although pay-for-performance (P4P) schemes have been implemented across low- and middle-income countries (LMICs), little is known about their distributional consequences. A key concern is that financial bonuses are primarily captured by providers who are already better able to perform (for example, those in wealthier areas), P4P could exacerbate existing inequalities within the health system. We examine inequalities in the distribution of pay-outs in Zimbabwe's national P4P scheme (2014-2016) using quantitative data on bonus payments and facility characteristics and findings from a thematic policy review and 28 semi-structured interviews with stakeholders at all system levels. We found that in Zimbabwe, facilities with better baseline access to guidelines, more staff, higher consultation volumes and wealthier and less remote target populations earned significantly higher P4P bonuses throughout the programme. For instance, facilities that were 1 SD above the mean in terms of access to guidelines, earned 90 USD more per quarter than those that were 1 SD below the mean. Differences in bonus pay-outs for facilities that were 1 SD above and below the mean in terms of the number of staff and consultation volumes are even more pronounced at 348 USD and 445 USD per quarter. Similarly, facilities with villages in the poorest wealth quintile in their vicinity earned less than all others-and 752 USD less per quarter than those serving villages in the richest quintile. Qualitative data confirm these findings. Respondents identified facility baseline structural quality, leadership, catchment population size and remoteness as affecting performance in the scheme. Unequal distribution of P4P pay-outs was identified as having negative consequences on staff retention, absenteeism and motivation. Based on our findings and previous work, we provide some guidance to policymakers on how to design more equitable P4P schemes.

Framework for identification and measurement of spillover effects in policy implementation: intended non-intended targeted non-targeted spillovers (INTENTS).

BACKGROUND: There is increasing awareness among researchers and policymakers of the potential for healthcare interventions to have consequences beyond those initially intended. These unintended consequences or "spillover effects" result from the complex features of healthcare organisation and delivery and can either increase or decrease overall effectiveness. Their potential influence has important consequences for the design and evaluation of implementation strategies and for decision-making. However, consideration of spillovers remains partial and unsystematic. We develop a comprehensive framework for the identification and measurement of spillover effects resulting from changes to the way in which healthcare services are organised and delivered. METHODS: We conducted a scoping review to map the existing literature on spillover effects in health and healthcare interventions and used the findings of this review to develop a comprehensive framework to identify and measure spillover effects. RESULTS: The scoping review identified a wide range of different spillover effects, either experienced by agents not intentionally targeted by an intervention or representing unintended effects for targeted agents. Our scoping review revealed that spillover effects tend to be discussed in papers only when they are found to be statistically significant or might account for unexpected findings, rather than as a pre-specified feature of evaluation studies. This hinders the ability to assess all potential implications of a given policy or intervention. We propose a taxonomy of spillover effects, classified based on the outcome and the unit experiencing the effect: within-unit, between-unit, and diagonal spillover effects. We then present the INTENTS framework: Intended Non-intended TargEted Non-Targeted Spillovers. The INTENTS framework considers the units and outcomes which may be affected by an intervention and the mechanisms by which spillover effects are generated. CONCLUSIONS: The INTENTS framework provides a structured guide for researchers and policymakers when considering the potential effects that implementation strategies may generate, and the steps to take when designing and evaluating such interventions. Application of the INTENTS framework will enable spillover effects to be addressed appropriately in future evaluations and decision-making, ensuring that the full range of costs and benefits of interventions are correctly identified.

Pediatric venous and arterial noncerebral thromboembolism in Denmark: a nationwide population-based study.

OBJECTIVE: To assess the incidence rate (IR), changes in IR over time, risk factors, treatment, and outcomes of pediatric noncerebral thromboembolism (TE). STUDY DESIGN: The study included all patients aged 0 to 18 years diagnosed with first-ever noncerebral venous thromboembolism (VTE) and/or arterial TE in Denmark between 1994 and 2006. Patients were identified in national registries, followed by validation of diagnoses by medical records review. RESULTS: We confirmed 331 cases of VTE and 46 cases of arterial TE during 15.8 million person-years of observation, with corresponding IRs of 2.09 and 0.29 per 100 000 person-years. The IR peaked in infancy (age <1 year) for both VTE and arterial TE, with an additional peak among adolescents (age 15 to 18 years) for VTE. Boys predominated in IR of VTE in infancy, whereas girls did so in adolescence (P < .01). The IRs of VTE and arterial TE remained stable during the study period, but with an trend toward increasing VTE in 2001 to 2006 (P = .064). Underlying diseases/external triggers were present in 86.6% of the patients, and thrombophilia was present in 47.9% of the VTE cases. All-cause and TE-related 30-day case fatalities were 4.0% and 1.6%, respectively. CONCLUSIONS: We found age- and sex-related disparities in the IRs of pediatric VTE and arterial TE, but insignificant changes in IR from 1994 to 2006.

A realist review to assess for whom, under what conditions and how pay for performance programmes work in low- and middle-income countries.

Pay for performance (P4P) programmes are popular health system-focused interventions aiming to improve health outcomes in low-and middle-income countries (LMICs). This realist review aims to understand how, why and under what circumstance P4P works in LMICs.We systematically searched peer-reviewed and grey literature databases, and examined the mechanisms underpinning P4P effects on: utilisation of services, patient satisfaction, provider productivity and broader health system, and contextual factors moderating these. This evidence was then used to construct a causal loop diagram.We included 112 records (19 grey literature; 93 peer-reviewed articles) assessing P4P schemes in 36 countries. Although we found mixed evidence of P4P's effects on identified outcomes, common pathways to improved outcomes include: community outreach; adherence to clinical guidelines, patient-provider interactions, patient trust, facility improvements, access to drugs and equipment, facility autonomy, and lower user fees. Contextual factors shaping the system response to P4P include: degree of facility autonomy, efficiency of banking, role of user charges in financing public services; staffing levels; staff training and motivation, quality of facility infrastructure and community social norms. Programme design features supporting or impeding health system effects of P4P included: scope of incentivised indicators, fairness and reach of incentives, timely payments and a supportive, robust verification system that does not overburden staff. Facility bonuses are a key element of P4P, but rely on provider autonomy for maximum effect. If health system inputs are vastly underperforming pre-P4P, they are unlikely to improve only due to P4P. This is the first realist review describing how and why P4P initiatives work (or fail) in different LMIC contexts by exploring the underlying mechanisms and contextual and programme design moderators. Future studies should systematically examine health system pathways to outcomes for P4P and other health system strengthening initiatives, and offer more understanding of how programme design shapes mechanisms and effects.

Venous thromboembolism after lower extremity orthopedic surgery: A population-based nationwide cohort study.

BACKGROUND: Venous thromboembolism (VTE) causes morbidity and mortality in the general population. Several events occur after lower limb orthopedic surgery, but the contribution from various types of lower limb surgery is not well known. OBJECTIVE: To investigate the postoperative incidence of VTE for all types of lower extremity orthopedic surgery compared with the background population. METHODS: Individual-level linkage of Danish nationwide register data for all Danish residents with first-time orthopedic surgery of the lower limb (1996-2017) and, for each of these, four controls from the general population matched on age, sex, and history of VTE. Adjusted hazard ratios (HR) compared the postoperative risk of VTE to the matched controls. RESULTS: In total 7203 of the 1 012 823 patients with a first orthopedic procedure had a VTE within 180 days after surgery, corresponding to a postoperative cumulative incidence of 0.71% (95% confidence interval [CI], 0.70-0.73). The cumulative incidence of VTE among controls was 0.11% (95% CI, 0.11-0.12). The HR of VTE within the first 30 days after surgery below knee level was 20.5 (95% CI, 17.9-23.5) compared with matched controls. The HRs of VTE after minor distal procedures (eg, meniscectomy and arthroscopies) were 2.9 (95% CI, 1.9-4.4) to 7.1 (95% CI, 6.4-8.0). CONCLUSION: All types of lower limb orthopedic surgery including minor distal procedures were associated with higher rates of VTE compared with matched controls, in particular within the first 30 days after surgery.

Prothrombotic genotypes and risk of venous thromboembolism in occult cancer.

BACKGROUND: Studies have reported that the combination of some prothrombotic genotypes and overt cancer yields a synergistic effect on VTE risk. Whether individual prothrombotic genotypes or number of risk alleles in a genetic risk score (GRS) affect VTE risk in occult cancer have not been addressed. The aim of this study was to investigate the joint effect of five prothrombotic genotypes and occult cancer on VTE risk. METHODS: Cases with incident VTE (n = 1566) and a subcohort (n = 14,537) were sampled from the Scandinavian Thrombosis and Cancer Cohort (1993-2012). Five single nucleotide polymorphisms previously reported in a GRS were genotyped: ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865) and F11 (rs2036914). Hazard ratios (HRs) for VTE by individual SNPs and GRS were estimated according to non-cancer and occult cancer (one year preceding a cancer diagnosis) exposure. RESULTS: Occult cancer occurred in 1817 subjects, and of these, 93 experienced a VTE. The VTE risk was 4-fold higher (HR 4.05, 95% CI 3.28-5.00) in subjects with occult cancer compared with those without cancer. Among subjects with occult cancer, those with VTE had a higher proportion of prothrombotic and advanced cancers than those without VTE. The VTE risk increased according to individual prothrombotic genotypes and GRS in cancer-free subjects, while no such effect was observed in subjects with occult cancer (HR for ≥4 versus ≤1 risk alleles in GRS: 1.14, 95% CI 0.61-2.11). CONCLUSIONS: Five well-established prothrombotic genotypes, individually or combined, were not associated with increased risk of VTE in individuals with occult cancer.

Association of smoking and cancer with the risk of venous thromboembolism: the Scandinavian Thrombosis and Cancer cohort.

Smoking is a well-established risk factor for cancer, and cancer patients have a high risk of venous thromboembolism (VTE). Conflicting results have been reported on the association between smoking and risk of VTE, and the effect of smoking on VTE-risk in subjects with cancer is scarcely studied. We aimed to investigate the association between smoking and VTE in subjects with and without cancer in a large population-based cohort. The Scandinavian Thrombosis and Cancer (STAC) cohort included 144,952 participants followed from 1993-1997 to 2008-2012. Information on smoking habits was derived from self-administered questionnaires. Active cancer was defined as the first two years following the date of cancer diagnosis. Former smokers (n = 35,890) and those with missing information on smoking status (n = 3680) at baseline were excluded. During a mean follow up of 11 years, 10,181 participants were diagnosed with cancer, and 1611 developed incident VTE, of which 214 were cancer-related. Smoking was associated with a 50% increased risk of VTE (HR 1.49, 95% CI 1.12-1.98) in cancer patients, whereas no association was found in cancer-free subjects (HR 1.07, 95% CI 0.96-1.20). In cancer patients, the risk of VTE among smokers remained unchanged after adjustment for cancer site and metastasis. Stratified analyses showed that smoking was a risk factor for VTE among those with smoking-related and advanced cancers. In conclusion, smoking was associated with increased VTE risk in subjects with active cancer, but not in those without cancer. Our findings imply a biological interaction between cancer and smoking on the risk of VTE.

Genetic susceptibility, smoking, obesity and risk of venous thromboembolism.

The F5 G1691A (Factor V Leiden) and F2 G20210A (prothrombin) mutations are linked to an increase in the incidence rate of venous thromboembolism (VTE), but their effects are highly variable. We investigated whether the effects of smoking and obesity might explain this variability. In a case-cohort study including the participants of the Danish Diet, Cancer and Health study, we computed incidence rates and Cox proportional hazard ratios for VTE in individuals with and without the mutations, categorized by weight and tobacco consumption. The sole effect of heavy smoking was 128 extra VTE events per 100,000 person years in individuals with the F5 G1691A mutation versus 59 in individuals without. The sole effect of obesity was 222 extra VTE events per 100,000 person years in individuals with the F5 G1691A mutation, versus 103 in individuals without this mutation; and 705 extra VTE events per 100,000 person years in individuals with the F2 G20210A mutation versus 107 in individuals without this mutation. The F5 G1691A and F2 G20210A mutations conferred increased susceptibility to the unfavourable effects of smoking and obesity on the risk for VTE. Thus, individuals with genetic risk factors for VTE might benefit from maintaining a healthy lifestyle.