Hazard Ratios For Venous Thromboembolism Research Articles

Long-term cardiovascular outcomes in survivors of 20 adult solid tumors: Large population-based matched cohort study.

11177 Background: The past few decades have seen notable advancements in how cancer is diagnosed and treated, with improvements in cancer survival. Cardiovascular diseases (CVDs) are the major life-limiting comorbidity among cancer survivors. Evidence is scarce on the risks of specific CVDs in survivors of a wide range of solid tumors, hindering informed strategies for prevention and management. Thus, we evaluated a large population-based U.S. electronic health records database. Methods: This large retrospective cohort study was conducted by using the TriNetX dataset between January 2008 and December 2022. All adult patients (>18 years) with a diagnosis of 20 most common solid tumors alive 12 months after diagnosis were matched with controls without a cancer history in a 1:1 ratio with these a priori identified potential confounders: demographics, BMI, nicotine dependence, comorbidities, labs, and medications. The primary outcome was the first incidence of CVD like heart failure (HF), major adverse cardiovascular events (MACE; unstable angina, myocardial infarction, or coronary artery intervention), or venous thromboembolism (VT), and cerebrovascular events (CVE; stroke, transient ischemic attack, cerebral infarction, carotid intervention). Hazard ratios (HR) were calculated to assess the outcomes. Results: 890126 individuals with a solid tumor of interest followed up at least 1 year later were identified and matched to 1787244 controls. The VT risk was higher among survivors of 18 out of 20 specific solid cancer types than controls. HRs ranged from HR 3.68( 95% CI 3.48-3.89) for kidney cancer and HR 1.27 (95% CI 1.21–1.35) in patients after pancreatic cancer. HRs for VT were more prominent without prior CVDs. Higher risks of CVDs were the most common immuno -and chemotherapy. Higher risk of HF was observed in lung (HR 1.46, 95% CI 1.32–1.89), liver (HR 1.22, 95% CI 1.18–1.26), and ovarian (HR 2.01, 95% CI 1.64–2.45) cancers and in patients younger than 55 years. Pericarditis and arrhythmia were common in lung, bile duct, and stomach cancers. A greater risk of arrhythmia was also observed in lung, kidney, and thyroid cancers, whereas CVE was observed in CNS cancers. Conclusions: Survivors of site-specific solid tumors are at a higher medium to long-term risk of one or more CVDs than the general population. Notably, substantial variations in risk were observed across different cancer primary sites. The outcomes underscore the importance of heightened monitoring for CVDs after a cancer diagnosis.

P1089 Disease characteristics at time of diagnosis of adult onset inflammatory bowel disease and the risk of venous thromboembolism in the modern era – A Swedish nationwide cohort study 2007-2021

Abstract Background Studies from mainly before the wide use of targeted therapies and guidelines for thromboprophylaxis indicate that patients with inflammatory bowel disease (IBD) are at a doubled risk of venous thromboembolism (VTE). We studied the risk of VTE in a modern-day cohort of patients with IBD, overall and in subgroups of disease characteristics. Methods Using Swedish healthcare registers, we identified a nationwide population-based cohort of 55,252 patients with incident IBD between 2007 and 2021 with a median follow-up time of 6.5 years. Patients were matched by age, sex, calendar year and county of residence with up to ten reference individuals from the general population (N=536,067). The primary outcome was VTE, including pulmonary embolism and deep vein thrombosis. Incidence rates per 1,000 person-years and hazard ratios (HR) were calculated for IBD in general and according to disease subtype, sex, age and disease characteristics at diagnosis. HRs stratified by matching variables (model 1) and additionally adjusted for comorbidities and socioeconomic factors (model 2) were estimated by using Cox regression. Results The incidence rate of VTE among patients with IBD was 5.03 per 1,000 person-years compared with 2.34 per 1,000 person-years among reference individuals (Table 1). This corresponded to a doubled incidence of VTE (HR=2.18, 95% confidence interval (CI)=2.07-2.29, model 1). Adjusting further for covariates in model 2 had only minor effects on the HR. The HR was consistent across IBD subtypes and sex. The relative risk was higher for those with younger age (18-39 years) at IBD diagnosis (HR 2.52, 95% CI: 2.22-2.83) with a risk difference of 1.25 per 1,000 person-years. The IR, 10.64 per 1,000 person-years, and risk difference, 5.42 per 1,000 person-years, was the highest for those with elderly onset (≥60 years) IBD. There was a stronger association for those with extensive ulcerative colitis (E3), primary sclerosing cholangitis, extraintestinal manifestations and perianal disease. HRs for VTE were persistently elevated across follow-up time, but was higher during the first year of follow-up (Figure 1). Conclusion The risk of VTE was doubled in these modern-day data and remained elevated across follow-up time. Disease characteristics associated with higher inflammatory burden at diagnosis and older age are markers of increased risk. This underscores the importance of continuous vigilance and individual assessment of risk factors for VTE in patients with IBD.

Ultra-processed food intake and incident venous thromboembolism risk: Prospective cohort study

Ultra-processed food (UPF) intake has been associated with multiple health outcomes, but data on the association between UPF intake and venous thromboembolism (VTE) risk are lacking. We conducted this study to examine the association between UPF intake and the risk of incident VTE. This prospective cohort study was based on 186,323 participants free of baseline VTE from the UK Biobank. UPF intake was assessed by 24-h recall questionnaires. Data on incident VTE came from the nationwide inpatient and primary care datasets and the death registry. Cox proportional hazards regression was used to estimate the association between UPF intake and incident VTE risk. Multiplicative interactions and stratified analyses by age, sex, and body mass index were performed. During a 10.5-year (median) follow-up, 4235 incident VTE cases were diagnosed. After adjusting for covariates, the hazard ratio of VTE among individuals with the highest quintile of UPF intake was 1.05 (95% confidence interval [CI] 0.94, 1.17) for UPF in servings, 1.12 (95% CI 1.01, 1.24) in grams, 1.10 (95% CI 1.00, 1.22) in grams %, 1.21 (95% CI 1.10, 1.33) in energy, and 1.15 (95% CI 1.05, 1.27) in energy % compared to those in the lowest quintile. Age, sex, and body mass index did not modify the associations (Pinteraction > 0.05). Higher UPF intake was associated with a moderately increased risk of VTE.

α1‐Antitrypsin Z allele and risk of venous thromboembolism in the general population

BackgroundThe α1‐antitrypsin Z (rs28929474) allele may lead to alterations in hemostasis either through liver disease or effects on coagulation factors. ObjectivesTo test the hypothesis that the α1‐antitrypsin Z genetic variant is associated with increased risk of venous thromboembolism. MethodsA total of 107 075 individuals from the Copenhagen General Population Study were used to test the association of the α1‐antitrypsin Z genetic variant with risk of venous thromboembolism, including deep venous thrombosis and pulmonary embolism, prospectively. Confirmatory analyses were done in the UK Biobank. ResultsDuring follow‐up, venous thromboembolism was diagnosed 6649 times in noncarriers, 436 times in heterozygotes, and 10 times in homozygotes. Hazard ratios for venous thromboembolism in α1‐antitrypsin Z heterozygotes and homozygotes versus noncarriers were 1.1 (95% confidence interval, 1.0–1.2) and 2.2 (1.3–3.7). A one Z allele increase was associated with a hazard ratio for venous thromboembolism of 1.2 (1.0–1.3). The corresponding odds ratio in the UK Biobank was 1.2 (1.1–1.3). The absolute risk of venous thromboembolism associated with α1‐antitrypsin ZZ homozygosity was 7.8% (3.6–12.1). The corresponding estimates were 20.1% (9.1–31.2) for prothrombin G20210A and 15.0% (12.6–17.4) for factor V Leiden. The fraction of venous thromboembolic events attributable to the α1‐antitrypsin Z allele was 0.7% (0.1–1.3). For the prothrombin G20210A and factor V Leiden mutations, population attributable fractions were 1.2% (0.9–1.6) and 10.5% (9.9–11.1). ConclusionIn conclusion, α1‐antitrypsin ZZ homozygosity was associated with a 2.2‐fold risk of venous thromboembolism and had a comparable population attributable fraction to prothrombin G20210A.

Risk of venous thromboembolism in Asian patients with inflammatory bowel disease: a nationwide cohort study

Routine prophylaxis for venous thromboembolism (VTE) in Asian IBD patients has been controversial. We aimed to estimate the risk of VTE of Asian patients at different phases of IBD by incorporating patient-specific risk factors. In this cohort study, we analyzed the National Health Insurance claims data between 2012 and 2016 for the entire Korean population. We calculated incidence rates and hazard ratios for VTE. The overall VTE risk was higher in patients with IBD [adjusted hazard ratio (aHR), 2.06; 95% confidence interval (CI), 1.66–2.55], than in controls. When we compare the risk of VTE by different disease phases, the risk of VTE was the highest during post-operation period after IBD-related bowel surgery (aHR, 39.7; 95% CI 9.87–159.3), followed by during hospitalized periods with flare (aHR, 27.2; 95% CI 14.9–49.65) and during hospitalized periods with non-flare (aHR, 16.23; 95% CI 10.71–24.58). The incidence rate (per 1000 person-years) was 15.26 during hospitalized periods with a flare and 9.83 during hospitalized periods with non-flare. According to age groups, the incidence rate (per 1000 person-years) during hospitalized periods with flare was 14.53 in young patients (20–39 years) and 34.58 in older patients (60–80 years). During hospitalized periods with non-flare, the incidence rate was 3.55 in young patients and 23.61 in older patients. The prophylaxis of VTE for Asian patients with IBD should be recommended in older patients admitted to hospital and be considered in young patients who are hospitalized with a flare.

Comorbidity and risk of venous thromboembolism after hospitalization for first‐time myocardial infarction: A population‐based cohort study

BackgroundMyocardial infarction (MI) is a risk factor for venous thromboembolism (VTE). Although comorbidities affect MI prognosis, it is unclear whether they affect VTE risk after MI. ObjectivesWe examined the impact of comorbidity on VTE risk after MI. MethodsWe used nationwide population‐based registries to identify first‐time hospitalizations for MI and subsequent occurrence of VTE in Denmark (1995‐2013). We included a comparison cohort from the general population matched 5:1 with MI patients by sex, age, and comorbidities. We computed 30‐day and 1‐ to 12‐month cumulative risks, rates, and hazard ratios of VTE. We also assessed the interaction between MI and comorbidity, defined as excess VTE risk in patients with both MI and comorbidity, by computing interaction contrasts and attributable fractions relating to the interaction. ResultsThirty‐day and 1‐ to 12‐month VTE risks were 0.6% and 0.5% in the MI cohort (n = 160 338) and 0.03% and 0.3% in the comparison cohort (n = 792 384). The 30‐day hazard ratio for VTE in the MI cohort was 23 (95% confidence interval, 20‐27), which decreased during 1‐year follow‐up. Thirty days after MI, interactions between MI and comorbidity accounted for 16% and 39% of VTE rates in MI patients with low‐to‐moderate and high comorbidity, respectively. The interactions were driven primarily by hemiplegia and cancer. ConclusionsThirty‐day VTE risk was substantially increased after MI compared with the general population. Although the absolute VTE risk was low, comorbidity substantially increased this risk, especially hemiplegia and cancer. VTE prophylaxis might be indicated in such high‐risk patients but warrants further investigation.

Mitigation of Venous Thromboembolism Risk through Favorable Lifestyle: The ARIC Study

Background: Venous thromboembolism (VTE) is a common disease with a strong genetic basis. Unhealthy lifestyle factors contribute to risk, but it is unknown whether healthier lifestyle can mitigate the risk for VTE in those at high genetic risk. We studied whether greater adherence to the American Heart Association's (AHA's) cardiovascular health metric called Life's Simple 7 (LS7) is associated with a lower rate of VTE in individuals with high genetic risk score (GRS) for VTE. Methods: We followed 9,026 middle-aged white participants from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective cohort of 15,792 individuals enrolled in 1987-89. A validated GRS was used, comprising 5 well known genetic conditions associated with VTE (factor V Leiden, prothrombin 20210A, non-O blood group, factor XI rs4241824, and fibrinogen gamma FGG rs2066865). Only white participants were included, as the GRS did not predict VTE in others. AHA's LS7 categories of inadequate, average, and optimal health were determined based on smoking status, body mass index, physical activity, diet, total cholesterol, blood pressure, and fasting glucose. VTE events were adjudicated by expert medical record review. We calculated hazard ratios (HRs) and 95% confidence intervals (CI) of incident VTE by LS7 categories, stratified by GRS (low, intermediate, high), adjusting for age, sex, and education. HRs were also calculated for individual LS7 components stratified by GRS. Results: There were 466 incident VTE over 22.8 years of follow-up. Compared to those with optimal health, those with inadequate LS7 score had higher rates of VTE (5.7% vs. 3.9%). In Figure 1, compared to the high GRS / inadequate LS7 group, the HR of VTE in the low GRS group with optimal health was lowest at 0.39 (95% CI 0.25-0.61), but moreover, the HR in the high GRS group with optimal health was also attenuated to 0.65 (95% CI 0.48-0.89). The pattern of association was similar for provoked and unprovoked VTE. Of the LS7 components, obesity was most strongly related to VTE. In Figure 2, compared to obese / high GRS participants, the HR of VTE with normal weight / low GRS was 0.36 (95% CI 0.23-0.57), while the HR in high GRS / normal weight participants was reduced by 45%, at 0.55 (95% CI 0.4-0.76). Conclusion: Among all participants, even those at high genetic risk, healthier lifestyle factors, particularly obesity, were associated with decreased incidence of VTE. Further studies should determine the impact of lifestyle change among patients at high genetic risk of VTE, such as in thrombophilic families. Disclosures Heckbert: National Institutes of Health: Other: Grants.

Enhanced VTE Risk Stratification in Ambulatory Patients with Cancer

Background: Ambulatory cancer patients initiating chemotherapy are at increased risk of venous thromboembolism (VTE). The Khorana score (0 = low, 1-2 = intermediate, 3-6 = high) helps clinicians to stratify these patients according to their underlying risk of VTE. The CATS score, which incorporates additional points for elevated biomarkers (d-dimer, p-selectin), may enhance VTE risk stratification by adding up to two additional points to the Khorana score. We sought to evaluate the incidence of VTE in patients with a Khorana score of ≥ 2 and elevated biomarkers. Methods: The AVERT trial compared apixaban to placebo for the primary prevention of VTE in ambulatory cancer patients with a Khorana score of ≥ 2. D-dimer and p-selectin measurements were performed at randomization. Patients with d-dimer or p-selectin over the 75th percentile received 1 additional point each per elevated measurement (d-dimer ≥ 2.06 ug/mL and p-selectin ≥ 44.5 ng/mL). Cumulative 6-month VTE incidences according to Khorana and CATS scores were calculated using Kaplan-Meier analysis. VTE was assessed among patients receiving placebo (control group) according to modified intention to treat analysis, whereas bleeding events were assessed among patients receiving apixaban according to per-protocol analysis. For both the Khorana and CATS scores, the highest risk groups were merged into pooled high-risk groups (Khorana ≥ 3, CATS ≥ 4) given the low number of patients in higher risk strata. Hazard ratios for VTE were calculated by univariate and multivariable Cox regression analyses. The linear association between risk scores, VTE incidence and incidence of overall bleeding was tested for statistical significance. Results: A total of 466 patients were included in the analysis, 229 and 237 patients in the placebo and apixaban arms, respectively. There were 73 (31.9%) and 86 (36.3%) patients with Khorana scores ≥ 3 in the control and apixaban arms, respectively, whereas there were 52 (22.7%) and 66 (27.9%) patients with CATS scores ≥ 4 in the control and apixaban arms, respectively. Mean age was 61.0 ± 11.8 and 60.6 ± 12.6 years in the control and apixaban arms, respectively. A minority of patients, 11.5% in the control arm and 15.1% in the apixaban arm, had ECOG scores of ≥ 2. The 6-month cumulative incidence of VTE was 13% (95% CI 7 to 23) in patients with a Khorana score of ≥ 3 and 20% (95% CI 11 to 35) in patients with a CATS score of ≥ 4, respectively (Figures 1 and 2). The linear trend for association of CATS risk scores with VTE was statistically significant (p = 0.0015). The linear trend for association of Khorana risk scores with VTE did not achieve statistical significance (p = 0.059). There was a total of 7 overall bleeding events (8.1%; 95% CI 2.4 to 13.9) in patients with a Khorana score of ≥ 3, two of which were major (2.3%; 95% CI 0 to 5.5). There were 7 overall bleeding events (10.6%; 95%CI: 3.2 to 18.0) in patients with a CATS score of ≥ 4, two of which were major (3.03%; 95%CI: 0 to 7.17). Neither increasing Khorana (p = 0.85, p = 0.69) or CATS scores (p = 0.58, p = 0.54) were significantly associated with either increased major or overall bleeding, respectively. Conclusion: Incorporation of d-dimer and p-selectin enhances VTE risk stratification in ambulatory cancer patients with a Khorana score of ≥ 2. Disclosures Carrier: BMS: Honoraria, Research Funding; Leo Pharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Servier: Honoraria. Key:Uniqure BV: Research Funding. Wells:BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria; Daiichi Sankyo: Honoraria.

OC3. Abstract Title: Enhanced VTE Risk Stratification in Ambulatory Patients with Cancer

<h3>Background</h3> Ambulatory cancer patients initiating chemotherapy are at increased risk of venous thromboembolism (VTE). The Khorana score (0 = low, 1-2 = intermediate, 3-6 = high) helps clinicians to stratify these patients according to their underlying risk of VTE. The CATS score, which incorporates additional points for elevated biomarkers (d-dimer, p-selectin), may enhance VTE risk stratification by adding up to two additional points to the Khorana score. We sought to evaluate the incidence of VTE in patients with a Khorana score of ≥ 2 and elevated biomarkers. <h3>Methods</h3> The AVERT trial compared apixaban to placebo for the primary prevention of VTE in ambulatory cancer patients with a Khorana score of ≥ 2. D-dimer and p-selectin measurements were performed at randomization. Patients with d-dimer or p-selectin over the 75th percentile received 1 additional point each per elevated measurement (d-dimer ≥ 2.06 ug/mL and p-selectin ≥ 44.5 ng/mL). Cumulative 6-month VTE incidences according to Khorana and CATS scores were calculated using Kaplan-Meier analysis. VTE was assessed among patients receiving placebo (control group) according to modified intention to treat analysis, whereas bleeding events were assessed among patients receiving apixaban according to per-protocol analysis. For both the Khorana and CATS scores, the highest risk groups were merged into pooled high-risk groups (Khorana ≥ 3, CATS ≥ 4) given the low number of patients in higher risk strata. Hazard ratios for VTE were calculated by univariate and multivariable Cox regression analyses. The linear association between risk scores, VTE incidence and incidence of overall bleeding was tested for statistical significance. <h3>Results</h3> A total of 466 patients were included in the analysis, 229 and 237 patients in the placebo and apixaban arms, respectively. There were 73 (31.9%) and 86 (36.3%) patients with Khorana scores ≥ 3 in the control and apixaban arms, respectively, whereas there were 52 (22.7%) and 66 (27.9%) patients with CATS scores ≥ 4 in the control and apixaban arms, respectively. Mean age was 61.0 ± 11.8 and 60.6 ± 12.6 years in the control and apixaban arms, respectively. A minority of patients, 11.5% in the control arm and 15.1% in the apixaban arm, had ECOG scores of ≥ 2. The 6-month cumulative incidence of VTE was 13% (95% CI 7 to 23) in patients with a Khorana score of ≥ 3 and 20% (95% CI 11 to 35) in patients with a CATS score of ≥ 4, respectively. The linear trend for association of CATS risk scores with VTE was statistically significant (p = 0.0015). The linear trend for association of Khorana risk scores with VTE did not achieve statistical significance (p = 0.059). There was a total of 7 overall bleeding events (8.1%; 95% CI 2.4 to 13.9) in patients with a Khorana score of ≥ 3, two of which were major (2.3%; 95% CI 0 to 5.5). There were 7 overall bleeding events (10.6%; 95%CI: 3.2 to 18.0) in patients with a CATS score of ≥ 4, two of which were major (3.03%; 95%CI: 0 to 7.17). Neither increasing Khorana (p = 0.85, p = 0.69) or CATS scores (p = 0.58, p = 0.54) were significantly associated with either increased major or overall bleeding, respectively. <h3>Conclusion</h3> Incorporation of d-dimer and p-selectin enhances VTE risk stratification in ambulatory cancer patients with a Khorana score of ≥ 2.

Concomitant Ro/SSA and La/SSB antibodies are biomarkers for the risk of venous thromboembolism and cerebral infarction in primary Sjögren's syndrome.

BackgroundTo assess the risk of incident cardiovascular disease in patients with primary Sjögren's syndrome, overall and stratified by Ro/SSA and La/SSB autoantibody status.MethodsA cohort of patients with primary Sjögren's syndrome in Sweden (n = 960) and matched controls from the general population (n = 9035) were included, and data extracted from the National Patient Register to identify events of myocardial infarction, cerebral infarction and venous thromboembolism. Hazard ratios were estimated using cox proportional hazard regressions.ResultsDuring a median follow‐up of 9.5 years, the overall hazard ratio (HR) was 1.6 (95% CI 1.2–2.1) for myocardial infarction, 1.2 (95% CI 0.9–1.7) for cerebral infarction and 2.1 (95% CI 1.6–2.9) for venous thromboembolism. Patients positive for both Ro/SSA and La/SSB autoantibodies had a substantially higher risk of cerebral infarction (HR 1.7, 95% CI 1.0–2.9) and venous thromboembolism (HR 3.1, 95% CI 1.9–4.8) than the general population. These risks were not significantly increased in Ro/SSA‐ and La/SSB‐negative patients. Among autoantibody‐positive patients, the highest HR of cerebral infarction was seen after ≥10 years disease duration (HR 2.8, 95% CI 1.4–5.4), while the HR for venous thromboembolism was highest 0–5 years after disease diagnosis (HR 4.7, 95% CI 2.3–9.3) and remained high throughout disease duration.ConclusionsPrimary Sjögren's syndrome is associated with a markedly increased risk of cardiovascular disease and the presence of Ro/SSA and La/SSB autoantibodies identify the subgroup of patients carrying the highest risk. These findings suggest that monitoring and prevention of cardiovascular disease in this patient group should be considered.

Lipoprotein(a) is not associated with venous thromboembolism risk

Objectives. Evidence from case-control studies as well as meta-analyses of these study designs suggest elevated lipoprotein(a) [Lp(a)] to be associated with an increased risk of venous thromboembolism (VTE). Prospective evidence on the association is limited, uncertain, and could be attributed to regression dilution bias. We aimed to assess the prospective association of Lp(a) with risk of VTE and correct for regression dilution. Design. We related plasma Lp(a) concentrations to the incidence of VTE in 2,180 men of the Kuopio Ischemic Heart Disease cohort study. Hazard ratios (HRs) (95% confidence intervals [CI]) were assessed and repeat measurements of Lp(a) at 4 and 11 years from baseline, were used to correct for within-person variability. Results. After a median follow-up of 24.9 years, 110 validated VTE cases were recorded. The regression dilution ratio of loge Lp(a) adjusted for age was 0.85 (95% CI: 0.82–0.89). In analyses adjusted for several established risk factors and potential confounders, the HR (95% CI) for VTE per 1 SD (equivalent to 3.56-fold) higher baseline loge Lp(a) was 1.06 (0.87–1.30). In pooled analysis of five population-based cohort studies (including the current study) comprising 66,583 participants and 1314 VTE cases, the fully-adjusted corresponding HR for VTE was 1.00 (95% CI: 0.94–1.07), with no evidence of heterogeneity between studies. Conclusions. Primary analysis as well as pooled evidence from previous studies suggest circulating Lp(a) is not prospectively associated with future VTE risk, indicating that evidence of associations demonstrated in case-control designs may be driven by biases such as selection bias.

Plasma Concentrations of High Molecular Weight Kininogen and Prekallikrein and Venous Thromboembolism Incidence in the General Population.

The kallikrein/kinin system, an intravascular biochemical pathway that includes several proteins involved in the contact activation system of coagulation, renin-angiotensin activation and inflammation, may or may not play a role in venous thromboembolism (VTE) occurrence. Within a large prospective population-based study in the United States, we conducted a nested case-cohort study to test the hypothesis that higher plasma levels of high molecular weight kininogen (HK) or prekallikrein are associated with greater VTE incidence. We related baseline enzyme-linked immunosorbent assay measures of HK and prekallikrein in 1993 to 1995 to incidence VTE of the lower extremity (n = 612) through 2015 (mean follow-up = 18 years). We found no evidence that plasma HK or prekallikrein was associated positively with incident VTE. HK, in fact, was associated inversely and significantly with VTE in most proportional hazards regression models. For example, the hazard ratio of VTE per standard deviation higher HK concentration was 0.88 (95% confidence interval = 0.81, 0.97), after adjustment for several VTE risk factors. Our findings suggest that plasma levels of these factors do not determine the risk of VTE in the general population.

The Risk of Venous Thromboembolism Is High in Chronic Lymphocytic Leukemia Because of Additional Cancers: A Danish National Cohort Study

Background: Venous thromboembolism (VTE) is a frequent yet potentially preventable complication that increases morbidity and mortality among cancer patients. Chronic Lymphocytic Leukemia (CLL) is a heterogeneous hematological cancer. Patient specific factors (age, gender, performance status) and CLL specific markers (e.g. IgHV mutational status, Binet stage, and beta 2-microglobulin (B2M) levels) influence the clinical course of CLL. A considerable proportion of CLL patients are diagnosed with additional cancer after the CLL diagnosis. The risk of VTE in CLL is higher than the background population throughout the clinical course of CLL in contrast to solid tumors where VTE typically develops within the first few months after cancer diagnosis.Aim: To investigate the risk of VTE in CLL patients according to patient specific factors, CLL specific markers, CLL treatment and additional cancer after the CLL diagnosis.Methods: The Danish National CLL Registry provided prospectively collected clinical data from all CLL patients diagnosed in Denmark since 2008. These data were linked at person level by the unique civil registration number to the Danish National Patient Registry for information on VTE and additional cancers, to the Danish National Prescription Database for information on prescribed and reimbursed anticoagulation treatment and to the Danish Civil Registration System for information on vital status and emigration. Study entry was date of CLL diagnosis; subjects were followed until VTE, death, emigration or administrative censoring. Cumulative incidence of VTE according to Binet stage, B2M levels, IgHV mutational status and additional cancers diagnosed later than CLL were calculated. Additional cancer after the CLL diagnosis was defined as a time-varying exposure. Subjects contributed to the number being at risk of VTE in the “no additional cancer” group until the possible date of additional cancer at which they shifted to the “additional cancer after CLL” group. Death and additional cancer were treated as competing risks by use of the Aalen-Johansen estimator. In Cox proportional hazard models, we estimated the hazard ratios (HR) of VTE; WHO-performance score, previous VTE and sex were included in the models as categorical variables, age was included as a continuous variable and anticoagulation treatment and additional cancer were included as time-varying covariates in the appropriate models.Results: From 2008 through 2015, 3609 subjects were diagnosed with CLL, 60.1% were males and the median age at CLL diagnosis was 70.4 years. Median follow-up was 2.6 years. During the study period, 12.7% (461) were diagnosed with an additional cancer and 19.9% (721) died. Anticoagulation treatment was given to 6.3% (227) of the CLL patients in the study period. The majority of the CLL patients had mutated IgHV, and B2M levels below 4mg/L (Table 1). A VTE was registered in 92 CLL patients during the study period. The cumulative incidence of VTE was highest in CLL patients exposed to additional cancer followed by CLL patients with B2M levels above 4 mg/L and unmutated IgHV. (Figure 1). CLL patients with additional cancer after the CLL diagnosis had a 3-4 fold higher risk of VTE compared with CLL patients without additional cancer. Previous VTE increased the risk of VTE after the CLL diagnosis by 5 fold. This was to some extent because a larger proportion of CLL patients with previous VTE were exposed to an additional cancer after the CLL diagnosis (23.9%) compared with the total study population (12.8%). The HR of VTE in case of previous VTE however, remained high after adjustment for additional cancer cancer and other risk factors (Table 1). Unmutated IgHV and B2M level >4 mg/L increased the risk of VTE, these associations persisted after adjustment for additional cancer (Table 1). CLL treatment tended to increase the risk of VTE, patient related factors and CLL specific markers did not affect the association markedly.Conclusion: The risk of VTE was especially high in CLL patients with additional cancer. Previous VTE was also a substantial (expected) risk factor whereas high age and CLL specific markers (B2M level > 4 mg/L, unmutated IgHV) were significant but less strong risk factors of VTE. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract MP18: The Risk of Venous Thromboembolism is Lower in Multiple Asian Ethnic Groups

Background: Several studies suggest a lower risk of venous thromboembolism (VTE) in Asians compared to other racial groups, and genetic mechanisms have been suspected. Despite their biological and cultural diversity, data have been sparse comparing risk of VTE among specific Asian ethnicities. Our previous report from 2000 on hospitalizations for VTEs in Asian Americans had included 337 subjects (all races) and numbers were insufficient to study specific Asian groups. We present here data from a new study with 4,674 VTE subjects. Hypothesis: Similar low VTE risk is present in multiple Asian ethnic groups. Methods: We studied composite VTE risk in 61,459 members of a comprehensive health plan, who had supplied self-classified ethnicity data on prior health examinations between 1978 and 1985 and had remained plan members in 1996, when outpatient diagnoses were added to computerized files. The subjects were 58% (n = 35,573) female and 42% (n= 25,886) male. From 1996 through 2015, at least one diagnosis of VTE was made during an outpatient visit or hospitalization for 4,675 persons. With Whites as the referent group, we performed logistic regressions controlled for age, sex, education, BMI, and smoking, yielding hazard ratios (HR) and 95% confidence intervals (CI). Results: The table shows HRs (CI) versus Whites (n=32,557) with 2,576 VTE. These lower HRs for VTE in Asians were generally similar in men and women. In the Asian stratum, a model with Chinese as referent showed an increased HR = 1.87 (1.09-3-21; p=0.02) for South Asians. Among covariates sex, education, and smoking were unrelated to VTE risk and BMI was positively associated; these results were similar in Whites, Blacks, and Asians. Conclusions: In conclusion, Chinese, Japanese, Filipinos and Other Asian Americans but not South Asians had substantially lower VTE risk compared to Whites. These data indirectly support a genetic explanation.

Complement C3 and High Risk of Venous Thromboembolism: 80517 Individuals from the Copenhagen General Population Study.

Complement activation may contribute to venous thromboembolism, including deep venous thrombosis and pulmonary embolism. We tested the hypothesis that high complement C3 concentrations are associated with high risk of venous thromboembolism in the general population. We included 80 517 individuals without venous thromboembolism from the Copenhagen General Population Study recruited in 2003-2012. Plasma complement C3 concentrations were measured at baseline, and venous thromboembolism (n = 1176) was ascertained through April 2013 in nationwide registries. No individuals were lost to follow-up. Complement C3 concentrations were approximately normally distributed, with a mean value of 1.13 g/L (interquartile range 0.98-1.26; SD 0.21). The cumulative incidence of venous thromboembolism was higher with progressively higher tertiles of complement C3 (log-rank trend: P = 3 × 10(-8)): at age 80, 7%, 9%, and 11% of individuals in the first, second, and third tertiles, respectively, had developed venous thromboembolism. Multivariable-adjusted hazard ratios for venous thromboembolism compared with individuals in the first tertile were 1.36 (95% CI, 1.16-1.59) for those in the second tertile and 1.58 (1.33-1.88) for those in the third tertile. Corresponding values were 1.36 (1.16-1.60) and 1.57 (1.33-1.87) after additional adjustment for C-reactive protein and 1.27 (1.09-1.49) and 1.31(1.10-1.57) after additional adjustment for body mass index. These results were similar for deep venous thrombosis and pulmonary embolism separately. The multivariable-adjusted hazard ratio for venous thromboembolism for a 1-g/L increase in complement C3 was 2.43 (1.74-3.40). High concentrations of complement C3 were associated with high risk of venous thromboembolism in the general population.

Epidemiology of Thrombosis in Aging

Aging is an important risk factor for venous thromboembolism (VTE). Data on age-specific incidence rates of VTE from population-based studies are limited. While it is well conceived that aging likely acts through Virchow's triad to increase VTE risk, the relative contribution of the components of Virchow's triad is not understood. The objectives of this study are three-fold. First, we calculated age-specific incidence of VTE (deep vein thrombosis and/or pulmonary embolism) using data from two large, prospective cohort studies: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) study. Second, we evaluated the contribution of coagulation factors VII and VIII, VWF, and activated partial thromboplastin time (aPTT) to age prediction of VTE risk. Third, we evaluated how aging influenced the prediction of VTE risk by confirmed genetic risk factors. We followed participants aged 45-64 years in ARIC (n=14,185) and ≥65 in CHS (n=5,414) at baseline visits (1987-89 in ARIC, 1989-90 and 1992-93 in CHS) for incident VTE through 2011 in ARIC and through 2001 in CHS. We computed person-years of follow-up from the date of the baseline examination to a censoring date. Genotype for the F5 Leiden and activity of coagulation factors (FVII:C and FVIII:C), VWF antigen, and aPTT were measured at baseline in ARIC. We performed proportional hazards regression to estimate the hazard ratio (HR) of VTE for baseline risk factors including age, the four hemostasis variables, and the F5 Leiden after adjusting for race and gender. The genetic analysis was stratified by race and follow-up time in both race groups, and additionally adjusted for principal components of population stratification in African Americans. ARIC participants developed 728 VTE events over 288,535 person-years of follow-up, and CHS participants developed 172 VTE events over 54,207 person-years of follow-up. Incidence rates of VTE per 1,000 person-years were 0.5, 1.0, 1.8, 2.8, 3.8, 5.4, 7.9, and 7.1 for 45-54, 55-59, 60-64, 65-69, 70-74, 75-79, 80-84, and 85-89 years in ARIC, respectively, and 0.8, 2.7, 2.7, 3.8, 6.2, and 5.7 for 65-69, 70-74, 75-79, 80-84, 85-89, and 90-99 years in CHS, respectively. The four hemostasis variables at baseline were significantly associated with baseline age (Pearson correlation coefficients -0.09 to 0.19, p<0.05) and future risk of VTE (p<0.05). Compared to the first quartile of baseline age distribution, the HRs of VTE with increasing quartile of age were 1.13 (95% CI 0.89-1.42), 1.92 (1.55-2.39), and 2.34 (1.89-2.92) for quartiles 2 to 4; the strength of association decreased after additional adjustment for FVII:C, FVIII:C, VWF, and aPTT: HRs 1.06 (0.84-1.34), 1.69 (1.36-2.11), and 1.97 (1.58-2.46), respectively. F5 Leiden was significantly associated with VTE risk in both whites and African Americans (p<0.05). The HRs for F5 Leiden were stronger for earlier follow-up (when the cohort was younger) than later follow-up in both race groups: whites: HR=4.59 (2.91, 7.25), 2.77 (1.88, 4.09), and 1.47 (0.69, 3.13) for first 10 years, second 10 years, and remaining ~5 years of follow-up, respectively; African Americans: HR=9.09 (2.00, 41.30), 2.14 (0.52, 8.79), and 6.10 (1.40, 26.47) for the three follow-up periods. In conclusion, our data suggest that contribution of aging to VTE risk is partly mediated through the coagulation pathway, and that the increased risk of VTE with aging is pushed to younger age by the presence of strong genetic predisposition (e.g. F5 Leiden). DisclosuresNo relevant conflicts of interest to declare.

Orthostatic Hypotension and Risk of Venous Thromboembolism in 2 Cohort Studies.

Although venous stasis is a risk factor for venous thromboembolism (VTE) and orthostatic hypotension (OH) can cause venous stasis, to our knowledge no study has examined the relationship between OH and VTE risk. We sought to quantify the association between OH and VTE (deep vein thrombosis or pulmonary embolism) using data from 2 large, prospective cohort studies: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) Study. We hypothesized that OH was positively associated with incident VTE. We measured OH-defined as a drop in systolic blood pressure (SBP) of at least 20 mm Hg or diastolic blood pressure (DBP) of at least 10 mm Hg within 3 minutes of standing-in participants aged 45-64 years in ARIC (n = 12,480) and ≥65 years in CHS (n = 5,027) at baseline visits (1987-1989 in ARIC; 1989-1990 and 1992-1993 in CHS), and followed participants for incident VTE (n = 568 in ARIC through 2011 and n = 148 in CHS through 2001). We calculated adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs) for incident VTE in relation to OH status. In CHS, there was a positive association between OH status and incident VTE (HR for VTE = 1.74 (95% CI: 1.20-2.51)). In contrast, there was no association between OH and VTE in the ARIC study (HR for VTE = 0.97 (95% CI: 0.70-1.33)). Community-dwelling older adults with OH had a moderately increased risk of VTE. These results were not seen in a population-based middle-aged cohort.

Impact of chemotherapy (CTX) on venous thromboembolism (VTE) and prognostic implications in patients with metastatic urinary tract tumors (UTT).

318 Background: VTE is common in cancer patients (incidence rate estimates 1-10%) and a leading cause of mortality in those receiving CTX. Little is known about the risk of VTE in patients with metastatic UTT. Understanding the frequency of VTE, whether CTX portends higher risk and impact on prognosis is of relevance. Methods: Data was collected via an electronic data capture platform from 25 centers. Patients diagnosed with metastatic UTT were eligible. Patients without a known date of diagnosis, last follow up, or VTE data were excluded. First-line treatment regimen was divided into 6 groups (Table). Cumulative and 90-day from metastatic disease diagnosis unadjusted VTE incidence rates were calculated. The impact of patient, therapy and tumor related factors were analyzed. A multivariate, competing risk regression was utilized to compute subdistribution hazard ratios (HR) of VTE risk for each treatment group. A VTE patient was matched to 4 non-VTE patients to carry out Kaplan-Meier survival analysis. Cases and controls were matched on survival from date of diagnosis of metastatic disease to date of VTE diagnosis and age group. Results: 1,762 patients were eligible. There were 144 (8.2%) and 60 (3.4%) events cumulative and within the first 90 days, respectively. Multivariate analysis revealed that non-urothelial histology and history of vascular disease were associated with increased risk. The HR for VTE based on treatment group, adjusted for covariates, is shown in the table. Overall survival was significantly worse in patients with VTE (p = 0.01). Conclusions: In metastatic UTT patients, there was no difference in VTE risk between CTX regimens. Development of VTE has negative impact on survival. [Table: see text]

Risks of venous thromboembolism in patients with liver cirrhosis: a nationwide cohort study in Taiwan

The results of various studies attempting to assess the risks of venous thromboembolism in liver cirrhosis have been conflicting. Furthermore, although the incidence of venous thromboembolism is thought to be low in Asians, the relationship between venous thromboembolism and liver cirrhosis has not been investigated in Asian countries. We investigated the risks of venous thromboembolism in cirrhotic patients in Taiwan to evaluate whether the risk is higher than in the general population. The data from 1,000,000 National Health Insurance beneficiaries were utilized. All adult beneficiaries were followed from 1 January 2007 to 31 December 2010 to identify those who developed venous thromboembolism. Each identified patient with liver cirrhosis was matched with 10 non-cirrhotic patients on the basis of high-dimensional propensity score. Cox regression models were applied to compare the hazards of venous thromboembolism in the matched cohorts. A total of 757,940 patients were enrolled. After matching, 2223 cirrhotic patients and 22,230 non-cirrhotic patients were selected. The adjusted hazard ratio of venous thromboembolism was significantly increased by having cirrhosis (1.71; 95% confidence interval [CI] 1.05-2.78). A subgroup analysis revealed a much higher hazard ratio of venous thromboembolism in an advanced cirrhosis subgroup (n = 293) than in a matched non-cirrhosis subgroup (n = 2930) (4.36; 95% CI 1.36-14.01). The risk of venous thromboembolism may be higher in Asian patients with cirrhosis than in the general Asian population, especially in those with advanced cirrhosis.

Prospective study of sickle cell trait and venous thromboembolism incidence

Sickle cell trait may increase risk of venous thromboembolism, but this is not fully established. We sought to determine the association of sickle cell trait with deep vein thrombosis and pulmonary embolism. Middle-aged African Americans participating in a prospective, population-based cohort investigation, the Atherosclerosis Risk in Communities Study, were followed from 1987 through 2011 for incident hospitalized pulmonary embolism (n = 111) or isolated deep vein thrombosis (n = 138), verified by physician review of medical records. Sickle cell trait (heterozygosity for hemoglobin S, n = 268) was compared with no sickle cell trait (n = 3748). Over a median of 22 years of follow-up, 249 participants had an incident venous thromboembolism. The hazard ratio of venous thromboembolism was 1.50 (95% confidence interval [CI] 0.96-2.36) for participants with vs. without sickle cell trait, after adjustment for age, sex, ancestry, hormone replacement therapy (women), body mass index, diabetes, and estimated glomerular filtration rate. This hazard ratio was 2.05 (95% CI 1.12-3.76) for pulmonary embolism and 1.15 (95% CI 0.58-2.27) for deep vein thrombosis without pulmonary embolism. Sickle cell trait in African Americans carries a 2-fold increased risk of pulmonary embolism but does not elevate deep vein thrombosis risk. Because neonatal screening for sickle hemoglobin is being conducted in the United States, consideration should be paid to the increased pulmonary embolism risk of individuals with sickle cell trait.