Varying Willingness to Pay Based on Severity of Illness: Impact on Health Technology Assessment Outcomes of Inpatient and Outpatient Drug Therapies in The Netherlands.

OBJECTIVES: Since 2015, Zorginstituut Nederland (ZIN) has linked disease severity ranges of 0.10 to 0.40, 0.41 to 0.70, and 0.71 to 1.00 with willingness-to-pay (WTP) reference values of €20 000, €50 000, and €80 000 per quality-adjusted life year gained, respectively. We sought to review whether these changes have affected ZIN health technology assessment (HTA) outcomes for specialist and outpatient drugs. METHODS: ZIN recommendations for specialist and outpatient drugs published between January 1, 2012, and December 31, 2020, that included a pharmacoeconomic report were reviewed. Data were extracted on disease severity, proportional shortfall calculation, reported WTP reference value, outcomes related to the cost-effectiveness of the product, budget impact, and ZIN's recommendation including rationale for their advice. RESULTS: A total of 51 HTAs were included. Of the 20 HTAs published before June 2015, a total of 9 received positive recommendations, 7 were conditionally reimbursed, and 4 received negative recommendations. None reported WTP reference values. Of the 31 evaluations published after June 2015, a total of 4 products received positive recommendations, 1 was conditionally approved, and 26 received negative recommendations initially. Most products (65%) reported disease severity to be >0.70. CONCLUSIONS: Since 2015, most products have fallen within the highest category of disease severity. Although pre-2015 outcomes were varied, post-2015 products overwhelmingly received negative recommendations, and the proportion of products for which price negotiations were recommended has increased. These differences in outcomes may result from the introduction of an explicit WTP reference value, whether or not in combination with the severity-adjusted ranges, but may also reflect other national policy changes in 2015.

Identification of coagulation gene 3'UTR variants that are potentially regulated by microRNAs.

MicroRNAs have been recognized as critical regulators of gene expression and might affect the risk of venous thrombosis. We aimed to identify 3' untranslated region (UTR) variants in coagulation genes that influence coagulation factor levels and venous thrombosis risk. The 3'UTR of coagulation genes were sequenced in subjects with extremely high or low plasma levels of these factors in two case-control studies. In total, 28 variants were identified. Five single nucleotide polymorphisms (SNPs) were predominantly present in one extreme level group (F2 rs1799963, F8 rs1050705 and F11 rs4253429, rs4253430 and rs1062547). Additional to F2 rs1799963, F8 rs1050705 (in men) and F11 rs4253430 were associated with an increased risk of venous thrombosis albeit confidence intervals were wide. The three F11 SNPs were in high linkage disequilibrium with functional variants rs2289252 and rs2036914. Rs1062547 and rs4253430 were associated with a significant increase of plasma FXI activity in heterozygotes and homozygotes in wild-type controls. In silico prediction revealed that these SNPs might disturb the binding sites of miR-544 and miR-513a-3p. Only miR-544 provoked a significant decrease of the luciferase activity that was not observed with a rs4253430 mutated vector. In conclusion, these results reinforce that microRNAs are candidates to play a role in haemostasis and complex disorders, such as thrombosis.

Role of hemostatic factors on the risk of venous thrombosis in people with impaired kidney function.

BACKGROUND: Factors explaining the association between impaired kidney function and venous thrombosis have not been identified so far. The aim of our study was to determine whether the association between impaired kidney function and venous thrombosis can be explained by the concurrent presence of genetic or acquired venous thrombosis risk factors. METHODS AND RESULTS: The glomerular filtration rate was estimated (eGFR) in 2473 venous thrombosis patients and 2936 controls from a population-based case-control study. Kidney function was grouped into 6 categories based on percentiles of the eGFR in the controls (>50th [reference], 10th-50th, 5th-10th, 2.5th-5th, 1st-2.5th, and <1st percentile). Several hemostatic factors showed a procoagulant shift with decreasing kidney function in controls, most notably factor VIII and von Willebrand factor. Compared with eGFR >50th percentile, factor VIII levels (adjusted mean difference, 60 IU/dL for the <1st eGFR percentile category) and von Willebrand factor levels (adjusted mean difference, 60 IU/dL for the <1st eGFR percentile category) increased with each percentile category. The odds ratios for venous thrombosis similarly increased across the categories from 1.1 (95% confidence interval, 0.9-1.3) for the 10th to 50th percentile to 3.7 (95% confidence interval, 2.4-5.7) for the <1st percentile category. Adjustment for factor VIII or von Willebrand factor attenuated these odds ratios, indicating an effect of eGFR on thrombosis through these factors. Adjustments for other risk factors for venous thrombosis did not affect the odds ratios. CONCLUSION: Impaired kidney function affects venous thrombosis risk via concurrently raised factor VIII and von Willebrand factor levels.

Multiple SNP testing improves risk prediction of first venous thrombosis.

There are no risk models available yet that accurately predict a person's risk for developing venous thrombosis. Our aim was therefore to explore whether inclusion of established thrombosis-associated single nucleotide polymorphisms (SNPs) in a venous thrombosis risk model improves the risk prediction. We calculated genetic risk scores by counting risk-increasing alleles from 31 venous thrombosis-associated SNPs for subjects of a large case-control study, including 2712 patients and 4634 controls (Multiple Environmental and Genetic Assessment). Genetic risk scores based on all 31 SNPs or on the 5 most strongly associated SNPs performed similarly (areas under receiver-operating characteristic curves [AUCs] of 0.70 and 0.69, respectively). For the 5-SNP risk score, the odds ratios for venous thrombosis ranged from 0.37 (95% confidence interval [CI], 0.25-0.53) for persons with 0 risk alleles to 7.48 (95% CI, 4.49-12.46) for persons with more than or equal to 6 risk alleles. The AUC of a risk model based on known nongenetic risk factors was 0.77 (95% CI, 0.76-0.78). Combining the nongenetic and genetic risk models improved the AUC to 0.82 (95% CI, 0.81-0.83), indicating good diagnostic accuracy. To become clinically useful, subgroups of high-risk persons must be identified in whom genetic profiling will also be cost-effective.

Type of arteriovenous vascular access and association with patency and mortality.

BACKGROUND: There are only a few risk factors known for primary patency loss in patients with an arteriovenous graft or fistula. Furthermore, a limited number of studies have investigated the association between arteriovenous access modality and primary patency loss and mortality. The aim of this study was to investigate risk factors for patency loss and to investigate the association between graft versus fistula use and outcomes (patency loss and mortality). METHODS: We prospectively followed 919 incident hemodialysis patients and calculated hazard ratios (HRs) for putative risk factors of primary patency loss using Cox regression. Furthermore, HRs were calculated to study the association between graft versus fistula use and two-year primary patency loss and two-year mortality. RESULTS: Cardiovascular disease, prior catheter use, lowest tertile of albumin, highest tertile of hsCRP, and lowest tertile of fetuin-A were associated with primary patency loss in both patients with grafts and fistulas. Increased age, female sex, and diabetes mellitus were only associated with primary patency loss in patients with a fistula. We did not observe an association between primary patency loss and BMI, residual GFR, levels of calcium, phosphorus, and total cholesterol. Furthermore, graft use as compared with fistula use was associated with an 1.4-fold (95% CI 1.0-1.9) increased risk of primary patency loss and with an 1.5-fold(95% CI 1.0-2.2) increased mortality risk. CONCLUSION: Cardiovascular disease, prior catheter use, albumin, hsCRP, and fetuin-A are risk factors for patency loss. Graft use as compared with fistula use was associated with an increased risk of patency loss and mortality.

A causal roadmap for generating high-quality real-world evidence.

Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized trials with outcomes assessed using RWD to fully observational studies. Yet, many proposals for generating RWE lack sufficient detail, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to prespecify study design and analysis plans; it addresses a wide range of guidance within a single framework. By supporting the transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on prespecified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers; three companion papers demonstrate applications of the Causal Roadmap for specific use cases.

Patterns of care in the management of seminoma stage I: results from a European survey.

UNLABELLED: Study Type - Therapy (practise pattern survey). Level of Evidence 3b. What's known on the subject? and What does the study add? The uncertainties about differences in relapse and rates of other late events such as second malignancy and cardiovascular events for the three post-orchidectomy strategies in seminoma stage I patients has led to debates about whether the three strategies are equally effective and safe. The differences in interpretation of the data as well as the debates are likely to result in differences in treatment after orchidectomy in seminoma stage I patient management. Current care patterns after orchidectomy are, however, unknown. We assessed patterns of care for seminoma stage I patients after orchidectomy by distributing a survey among doctors treating such patients across Europe. The 969 respondents showed large differences in care strategies between specialties and countries that indicate the need for research into long-term relapse rates and long-term adverse effects to standardize and optimize care for seminoma stage I patients. OBJECTIVE: • To assess precise patterns of care after orchidectomy in Europe for stage I seminoma patients, we aimed to perform a survey among doctors in the various European countries. PATIENTS AND METHODS: • We distributed a survey in 2009 and 2010 among American Society of Clinical Oncology and European Association of Urology members. RESULTS: • In total, 969 questionnaires were included in the analysis. More than half of the 969 physicians (58%) currently offer only one post-surgical treatment: 18% only surveillance, 19% only radiotherapy and 21% only chemotherapy. Thirteen percent of the 969 physicians currently offer all three strategies, 25% offer surveillance and adjuvant radiotherapy or chemotherapy, and 5% offer either adjuvant radiotherapy or chemotherapy without surveillance. • We found large differences in care patterns between specialties and countries. Even within countries, care after orchidectomy was not standardized. • Before 2005, 73% of the physicians offered only one treatment and of those 51% gave adjuvant radiotherapy. CONCLUSIONS: • Large differences in pattern of care after orchidectomy for stage I seminoma patients exist between specialties and countries within Europe. • More information on long-term relapse rates and long-term adverse effects of the three strategies is needed to standardize and optimize care after orchidectomy.

Cell adhesion molecule 1: a novel risk factor for venous thrombosis.

Protein C (PC) deficiency increases the risk of venous thrombosis (VT) among members of Kindred Vermont II but fails to fully account for the inheritance pattern. A genome scan of the pedigree supported the presence of a prothrombotic gene on chromosome 11q23 (nominal P < .0001), with weaker support on chromosomes 10p12 (P < .0003) and 18p11.2-q11 (P < .0007). Resequencing of 109 genes in the linkage regions identified 5030 variants in a sample of 20 kindred members. Of 16 single nucleotide polymorphisms in 6 genes tested in the larger family set, only single nucleotide polymorphisms in cell adhesion molecule 1 (CADM1) associated with VT. Among the 8 CADM1 single nucleotide polymorphisms genotyped in the complete sample, rs6589488 was most strongly supported (P < .000007), but the association was limited to the PC-deficient subset of the sample (P < .000001). Haplotype analysis narrowed the region containing the causative variant to the coding region of the CADM1 gene. CADM1 gene expression analyzed in blood outgrowth endothelial cells cultured from family members was decreased compared with control subjects, lending phenotypic support to this conclusion. Finally, we have for the first time demonstrated CADM1 in endothelial cells, where it appears to be selectively involved in endothelial cell migration, suggesting a role in endothelial barrier repair.

Association between type II secretory phospholipase A2 plasma concentrations and activity and cardiovascular events in patients with coronary heart disease.

AIMS: Type II secretory phospholipase A(2) (sPLA(2)-IIA) is widely expressed in various cell types and may trigger local inflammatory responses. We sought to evaluate whether systemic sPLA(2) is associated with prognosis in patients with coronary heart disease (CHD). METHODS AND RESULTS: Plasma concentrations of sPLA(2) (ELISA) and sPLA(2) activity (selective fluorometric assay) were measured at baseline in a cohort of 1024 patients aged 30-70 years with CHD. The Cox-proportional hazards model was used to determine the prognostic value of sPLA(2) on a combined cardiovascular disease (CVD) endpoint after adjustment for covariates. During a mean follow-up of 4.1 years, 93 patients (9.1%) experienced a secondary CVD event. In a multivariable model, sPLA(2) mass and activity were associated with hazard ratios of secondary CVD events of 2.07 (95% CI, 1.17-3.66) and 1.65 (95% CI 0.96-2.84) for mass and activity, respectively, when extreme tertiles were compared. Further adjustment for cystatin C, N-terminal-probrain natriuretic peptide, C-reactive protein, and lipoprotein-associated phospholipase A(2) attenuated the associations, still showing a positive trend for mass but a less clear pattern for activity. However, when sPLA(2) mass and activity were analysed as continuous variables both still showed a statistically significant increase in risk in all models. CONCLUSION: Secretory phospholipase A(2) mass and activity appear to be predictive of secondary CVD events in patients with CHD.

Exclusion of the alpha2 subunit of platelet-activating factor acetylhydrolase 1b (PAFAH1B2) as a prothrombotic gene in a protein C-deficient kindred and population-based case-control sample.

Protein C deficiency increases the risk of venous thromboembolic disease among members of Kindred Vermont II, but fails to fully account for the inheritance pattern. A genome scan of the pedigree supported the presence of a prothrombotic gene on chromosome 11q23 (107-119 Mb, nominal P < 0.0001), with weaker support on chromosomes 10p12 (11-25 Mb, P < 0.0003) and 18p11.2-q11 (12-24 Mb, P < 0.0007). The 11q23 region contains the alpha(2) subunit (gene name PAFAH1B2) of platelet-activating factor acetylhydrolase 1b, a candidate prothrombotic gene. Re-sequencing of the PAFAH1B2 regulatory region in 137 pedigree members, including 25 thrombosis cases, revealed 12 variants; eight were present in only 0-2 affected individuals; the other four assorted into three haplotypes and included three variants predicted to destroy transcription factor-binding sites. More extensive re-sequencing of the PAFAH1B2 gene in 11 affected and five unaffected pedigree members revealed an additional 13 variants that assorted into the same three haplotypes. We rejected as thrombosis risk factors each of the three presumed destructive variants as well as each of the three haplotypes. We also rejected (odds ratio = 1.31 CI: 0.91-1.88) one of the three variants in 469 cases and 472 controls from the Leiden Thrombophilia Study (LETS). Therefore, PAFAH1B2 is not the gene responsible for the linkage evidence on chromosome 11q23.

Using the common-sense model to predict risk perception and disease-related worry in individuals at increased risk for venous thrombosis.

OBJECTIVE: This study applied the Common-Sense Model (CSM) to predict risk perception and disease-related worry in 174 individuals with a genetic predisposition to venous thrombosis (thrombophilia). DESIGN: Participants completed an adapted version of the Illness Perception Questionnaire-Revised (IPQ-R) and measures assessing risk perception and worry. RESULTS: Regression analyses revealed that illness perceptions were predictors of risk perception and thrombosis worry. The hypothesis that illness perceptions mediate the relationship between a person's experience of venous thrombosis and perceived risk and thrombosis worry could not be confirmed. CONCLUSIONS: Further research should refine the IPQ-R for populations at risk of a disease and examine the value of the CSM in explaining the relationship between risk perception, worry, and health behavior.

Recurrence rate after a first venous thrombosis in patients with familial thrombophilia.

OBJECTIVE: Few comprehensive data are available on the recurrence rate of venous thrombosis in carriers of thrombophilic defects from thrombophilic families. We prospectively determined the recurrence rate after a first venous thrombotic event in patients with familial thrombophilia attributable to factor V Leiden or deficiencies of protein C, S, or antithrombin. METHODS AND RESULTS: Data were gathered during follow-up on the occurrence of risk situations, anticoagulation treatment, and events (eg, venous thrombosis, hemorrhage). Over a mean follow-up period of 5.6 years, 44 of the 180 patients with familial thrombophilia who did not use long-term anticoagulation experienced a recurrent venous thromboembolic event (5.0%/year; 95% CI 3.6 to 6.7) compared with 7 of the 124 patients on long-term anticoagulation (1.1%/year; 95% CI 0.4 to 2.2). Spontaneous events occurred less often in patients on long-term anticoagulation (57%) than in patients without long-term anticoagulation (75%). The highest recurrence rate was found among men with a deficiency in natural anticoagulants or multiple defects and women with antithrombin deficiency. Although long-term anticoagulation treatment decreased the incidence of recurrent events by 80%, it also resulted in a risk of major hemorrhage of 0.8% per year. CONCLUSIONS: Extra care after a first event is required for men with a deficiency in natural anticoagulants or multiple defects and women with antithrombin deficiency.

Normal retinal vasculature despite familial protein C deficiency.

PURPOSE: It is unclear whether protein C deficiency is associated with retinal venous occlusive disease. DESIGN: We performed a cross-sectional study. METHODS: Members of a protein C-deficient family, either deficient or nondeficient, with a history of nonocular venous thrombosis were included. All participants completed questionnaires regarding their medical and ophthalmic histories. Each subject underwent dilated direct ophthalmoscopic and binocular indirect ophthalmoscopic examinations by a single vitreoretinal specialist. RESULTS: None of the 18 family members with a known history of nonocular thrombosis-12 with and 6 without protein C deficiency- manifested stigmas of recent or chronic retinal vascular occlusive disease. CONCLUSIONS: This study showed no evidence of involvement of the retinal vascular bed in a family with an increased risk of nonocular venous thrombosis attributable to the deficiency of protein C.

The impact of venous thrombosis on quality of life.

Quality of life (QOL) is increasingly seen as an important outcome in clinical care. Etiology, diagnosis, and management of venous thrombosis have been studied extensively, but only few studies have examined the impact of venous thrombosis on quality of life. The purpose of this study was to examine the impact of venous thrombosis on quality of life in a well-defined population of patients with venous thrombosis, by using both a generic and a disease-specific quality of life measure. A total of 45 patients from the thrombosis clinic of the University of Vermont in Burlington, VT, returned a mailed questionnaire including the Short-Form 36 (SF-36) and a disease-specific venous thrombosis-quality of life (VT-QOL) questionnaire about the problems faced by patients with venous thrombosis. The sample consisted of 13 men (28.9%) and 32 women (71.1%). The mean age was 44.1 years, with a range from 21 to 80 years. Compared with population norms of a general U.S. population that were adjusted for age and sex (N= 2463), venous thrombosis patients scored significantly lower (p < 0.05) on all subscales of the SF-36. Patients with the postthrombotic syndrome (PTS) appeared to have more impairment in their quality of life as measured by both the SF-36 and the disease-specific questionnaire. All correlations between the SF-36 subscales and the subscales of the VT-QOL were significant, most of them on a p < 0.01 level. Given the impact of venous thrombosis and the postthrombotic syndrome on quality of life, assessment of QOL should be included in future studies on the outcome of venous thrombosis.

No effect of the prothrombin G20210A mutation on protein C activation in a large kindred with type I protein C deficiency.

Previously, we observed a positive association of prothrombin concentrations with thrombin generation (fragment 1 + 2) and thrombin activity (fibrinopeptide A), but no association with protein C activation peptide levels. We further evaluated a potential beneficial effect of increased prothrombin concentrations on activated protein C generation by assessing the plasma concentration of activated protein C in complex with protein C inhibitor (APC-PCI). Blood samples were used from 195 family members of a large French-Canadian kindred with type I protein C deficiency due to a 3363C insertion in the protein C gene. We utilized a new and highly sensitive assay for measuring the concentration of APC-PCI complex as a measure of the level of activation of protein C. Means of the plasma concentrations of the APC-PCI complex were compared among carriers and non-carriers of the prothrombin G20210A mutation. Protein C activity levels were positively associated with APC-PCI complex plasma concentrations; however, APC-PCI complex levels were not different for carriers of the prothrombin G20210A mutation than for non-carriers. Thus, carriers of the prothrombin G20210A mutation do not have increased protein C activation despite the increased thrombin generation resulting from the higher prothrombin concentrations associated with the G20210A mutation.

Genetic variants in Cell Adhesion Molecule 1 (CADM1): a validation study of a novel endothelial cell venous thrombosis risk factor.

INTRODUCTION: In a protein C deficient family, we recently identified a candidate gene, CADM1, which interacted with protein C deficiency in increasing the risk of venous thrombosis (VT). This study aimed to determine whether CADM1 variants also interact with protein C pathway abnormalities in increasing VT risk outside this family. MATERIALS AND METHODS: We genotyped over 300 CADM1 variants in the population-based MEGA case-control study. We compared VT risks between cases with low protein C activity (n=194), low protein S levels (n=23), high factor VIII activity (n=165) or factor V Leiden carriers (n=580), and all 4004 controls. Positive associations were repeated in all 3496 cases and 4004 controls. RESULTS: We found 22 variants which were associated with VT in one of the protein C pathway risk groups. After mutual adjustment, six variants remained associated with VT. The strongest evidence was found for rs220842 and rs11608105. For rs220842, the odds ratio (OR) for VT was 3.2 (95% CI 1.2-9.0) for cases with high factor VIII activity compared with controls. In addition, this variant was associated with an increased risk of VT in the overall study population (OR: 1.5, 95% CI 1.0-2.2). The other variant, rs11608105, was not associated with VT in the overall study population (OR: 1.0, 95% CI 0.8-1.1), but showed a strong effect on VT risk (OR: 21, 95% CI 5.1-88) when combined with low protein C or S levels. CONCLUSIONS: In a population-based association study, we confirm a role for CADM1 variants in increasing the risk of VT by interaction with protein C pathway abnormalities.

Single nucleotide variants in the protein C pathway and mortality in dialysis patients.

BACKGROUND: The protein C pathway plays an important role in the maintenance of endothelial barrier function and in the inflammatory and coagulant processes that are characteristic of patients on dialysis. We investigated whether common single nucleotide variants (SNV) in genes encoding protein C pathway components were associated with all-cause 5 years mortality risk in dialysis patients. METHODS: Single nucleotides variants in the factor V gene (F5 rs6025; factor V Leiden), the thrombomodulin gene (THBD rs1042580), the protein C gene (PROC rs1799808 and 1799809) and the endothelial protein C receptor gene (PROCR rs867186, rs2069951, and rs2069952) were genotyped in 1070 dialysis patients from the NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort) and in 1243 dialysis patients from the German 4D cohort. RESULTS: Factor V Leiden was associated with a 1.5-fold (95% CI 1.1-1.9) increased 5-year all-cause mortality risk and carriers of the AG/GG genotypes of the PROC rs1799809 had a 1.2-fold (95% CI 1.0-1.4) increased 5-year all-cause mortality risk. The other SNVs in THBD, PROC, and PROCR were not associated with 5-years mortality. CONCLUSION: Our study suggests that factor V Leiden and PROC rs1799809 contributes to an increased mortality risk in dialysis patients.

Asymmetric and symmetric dimethylarginine and risk of secondary cardiovascular disease events and mortality in patients with stable coronary heart disease: the KAROLA follow-up study.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor, which has been associated with total and cardiovascular mortality in various clinical settings. Studies on its structural isomer, symmetric dimethylarginine (SDMA), are scarce. This study aimed to determine the associations of both ADMA and SDMA levels with secondary cardiovascular disease events and all-cause mortality in patients with stable coronary heart disease (CHD). METHODS: In the observational prospective cohort study KAROLA, 1,148 CHD patients were followed for a median of 8.1 years. ADMA and SDMA were determined by liquid chromatography-tandem mass spectrometry. Baseline ADMA and SDMA levels were categorized in quartiles or standardized by their respective standard deviation, and appropriate hazard ratios and 95 % confidence intervals (HR [95 % CI]) were estimated in Cox proportional hazards models. RESULTS: 150 patients experienced secondary cardiovascular disease events (CVD) and 121 patients died. After adjustment for confounders, ADMA was not associated with the risk of secondary CVD events (HR per standard deviation increase: 1.02 [95 %CI: 0.86-1.21]), whereas an association was suggested for SDMA (HR 1.17 [1.00-1.37]). Higher hazard ratios were observed in all-cause mortality models (ADMA: HR 1.15 [0.95-1.37]; SDMA: HR 1.29 [1.09-1.52]). CONCLUSIONS: Our results suggest that especially SDMA might possibly have potential as a risk marker for all-cause mortality and to a lesser extent for secondary cardiovascular events. Future studies are needed to quantify these associations more precisely and should, in particular, further address the possibility of residual confounding by impaired kidney function.

Flow-simulated thrombin generation profiles as a predictor of thrombotic risk among pre-menopausal women.

A large number of individuals are at risk for deep venous thrombosis (DVT) due to alterations in multiple coagulation factors and inhibitors secondary to malignancy, drug interactions, or other general medical conditions. Traditional metrics of haemostasis such as prothrombin time, partial thromboplastin time, and bleeding time, generally estimate anticoagulation status and bleeding risk rather than thrombosis risk. The objective of this study was to correlate a novel, systems-based metric of clotting potential to risk of DVT from a database derived from the Leiden Thrombophilia Study (LETS). We utilised a computational model of blood coagulation, which addresses the interplay between biochemical factors, blood flow, and physiologic surface initiation of coagulation, to calculate an individualised, systems-based metric of clotting potential, termed the flow-simulated thrombin generation (FSTG), for 210 pre-menopausal women in LETS. Both DVT and oral contraceptive (OC) use were associated with higher values of FSTG. We demonstrated a nearly three-fold increased risk of DVT for each standard deviation increase above the mean in FSTG determined under venous flow conditions, which remained highly predictive after adjustment for age and OC status (adjusted odds ratio 2.66; 95% confidence interval 1.69-4.19; p<0.0001). In conclusion, a systems-based screening approach that integrates biochemical factors and flow haemodynamics identifies small subgroups of patients at risk of thrombosis that may benefit from oral anticoagulants.

Clotting factor gene polymorphisms and colorectal cancer risk.

PURPOSE: Increased coagulation has been associated with cancer onset and progression. Mainly small studies have addressed the association between clotting factor gene polymorphisms and the onset of colorectal cancer. We examined the association between six well-known clotting factor gene polymorphisms and colorectal cancer risk in a large case-control study. PATIENTS AND METHODS: Factor V Leiden (rs6025), prothrombin G20210A (rs1799963), PAI-1 4G/5G (rs1799889), MTHFR 677C>T (rs1801133), fibrinogen gamma 10034C>T (rs2066865), and factor XIII Val34Leu (rs5985) were genotyped in 1,801 patients with colorectal cancer and 1,853 healthy controls from a large German population-based study. The risk of colorectal cancer associated with gene variants was determined by calculating odds ratios (ORs) and their 95% CIs using logistic regression. RESULTS: Homozygous carriers of the prothrombotic factor V Leiden polymorphism showed a 5.8-fold increased risk (95% CI, 1.69 to 19.72) for colorectal cancer compared with noncarriers. A 30% reduced risk was found for heterozygous carriers of factor V Leiden (OR = 0.68; 95% CI, 0.52 to 0.90) and prothrombin G20210A (OR = 0.69; 95% CI, 0.49 to 0.96), implying an advantage for slightly increased thrombin generation. Carriers of the antithrombotic factor XIII Val34Leu polymorphism showed a 15% reduced risk of developing colorectal cancer (OR = 0.85; 95% CI, 0.74 to 0.97) compared with noncarriers. Our results did not support an effect of PAI-1 4G/5G, MTHFR 677C>T, and fibrinogen gamma 10034C>T on colorectal cancer risk. CONCLUSION: Our results support a role of clotting factor polymorphisms and thereby the coagulation system in the risk of colorectal cancer.