ALBERT

Description: Key Points Patients with VT have an increased risk of subsequent CVD compared with control participants. The increased risk of CVD in these patients can be explained by etiologic factors leading to both diseases.

Description: Key Points Superficial vein thrombosis combined with an acquired thrombotic risk factor increases the risk of venous thrombosis 10- to 100-fold. If confirmed, these findings have important implications for the future prevention of venous thrombosis.

Description: Key Points In the 3 months after isolated SVT, the risk of a deep venous event or pulmonary embolism is 3.4%. This risk remains fivefold increased more than 5 years after the superficial event.

Description: Background: Several studies have shown a high incidence of venous thromboembolism (VTE) in hematological cancers, comparable with solid cancers, although bleeding is also a prominent complication of the hematological patients. Cancer patients, who develop VTE, have a reduced survival and impaired quality of life if compared to those who do not develop VTE. Hematological cancers are rather rare diseases and most studies have described only some of the entities. Here we want to compare the incidence of VTE in seven subtypes in a large cohort. Aim: To investigate the risk of VTE in hematological malignancies compared to matched controls in a prospective population based cohort study, the Scandinavian Thrombosis and Cancer (STAC) Cohort. Methods: TheSTAC Cohort includes 144.952 participants from three population based prospective cohort studies, i.e. The Tromsø Study and the HUNT2 study from Norway, and the Danish Diet, Cancer and Health Study. The participants were enrolled during 1993-1997, and mean follow-up time was 11.7 years. The cohort profile and outcome of first time objectively confirmed VTE events have been described in prior studies. For this study we collected data from the national cancer registries using morphology codes to identify cohort subjects with hematological cancers, divided into 7 groups: multiple myeloma (MM), chronic lymphocytic leukemia (CLL), acute leukemia (myeloid and lymphoblastic) (AL), chronic myeloproliferative neoplasms and myelodysplastic syndrome (CMN/MDS), aggressive non-Hodgkin lymphoma (aggr. NHL), Hodgkin lymphoma (HL), and indolent lymphoma (Ind. L). Subjects with a VTE event more than one year before cancer diagnosis were excluded. For each of the cases 5 controls matched on country, sex and age were identified. We used Cox regression models to estimate the relative risk of VTE across the seven different subtypes of hematological malignancies with a time axis starting one year before the diagnosis of cancer (and similar for matched controls) and ending at a VTE event or end of follow-up. Data were adjusted for age by spline regression. Results: During follow-up 891 participants were diagnosed with a hematological malignancy, and in this group 41 VTE events were observed corresponding to an incidence of 12.0 events per 1000 person-years (10-3 p-y). In the control group of 4455 participants 55 VTE events were observed which gave an incidence of events on 2.3* 10-3 p-y. Having a hematological cancer including all seven investigated types was associated with a six-fold increased risk of developing VTE compared to the matched controls. During follow-up 203 participants were diagnosed with MM, and 10 VTE events were observed giving an event rate of 14.6*10-3 p-y; hazard ratio (HR) for VTE was 7.2, 95% confidence interval (CI): 3.6-14.3. CLL was diagnosed in 176 cases, and 11 VTE events were observed in this group (event rate 11.5*10-3 p-y; HR 5.3; 95% CI: 2.7-10.1). Among the 63 participants who were diagnosed with AL during follow-up 2 VTE events were observed corresponding to an event-rate on 12.8*10-3 p-y; (HR 6.9; 95% CI: 1.7-29.0). In the group of CMN/MDS 4 VTE events were observed among 104 patients (event-rate 12.0*10-3 p-y; HR 6.4, 95% CI: 2.3-18.0). In aggressive NHL 10 VTE events were observed among 158 patients resulting in an event-rate of 18.9*10-3 p-y (HR 10.4; 95% CI: 5.2-20.8). Forty-four participants were diagnosed with HL, and 2 VTE events were observed which corresponds to an event-rate of 10.6*10-3 p-y among these patients (HR 5.1; 95% CI: 1.2-21.4). Indolent lymphoma was diagnosed in 143 subjects, and 2 VTE events were observed (event-rate 3.5*10-3 p-y; HR 1.9; 95% CI: 0.47-8.0). The results are summarized in the table: Table. MM CLL AL CMN/MDS Aggr. NHL HL Ind. L N 203 176 63 104 158 44 143 VTE (n) 10 11 2 4 10 2 2 Incidence (*10-3 p-y) 14.6 11.5 12.8 12.0 18.9 10.6 3.5 HR 7.2 5.3 6.9 6.4 10.4 5.1 1.9 95 % CI 3.6-14.3 2.7-10.1 1.7-29.0 2.3-18.0 5.2-20.8 1.2-21.4 0.47-8.0 Conclusion: Indolent lymphoma was the only investigated hematological malignancy that was not associated with a significant increased risk of VTE. The other types of hematological malignancies had an increased risk of VTE ranging from approximately 5-10 times, highest in aggressive non-Hodgkin lymphoma and lowest in Hodgkin lymphoma. However a limitation of the study is the small numbers in some of the groups in spite of the large cohort. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 1149 Background: Antithrombotic prophylaxis needs to be balanced against bleeding risk. Therefore, risk stratification is useful to identify patients who would benefit most. In this study, we analyzed how VT risk relates to different leukocyte count. We also analyzed the effect of high leukocyte counts in groups with high risk of VT. Methods: In the MEGA case-control study, blood leukocyte count and information on environmental risk factors were collected from 2443 patients with VT and 1459 partner controls. Logistic regression analyses were adjusted for age and sex. Results: Population characteristics are detailed in Table 1. Risk of VT increased for measurements above the 97.5th percentile for total white cells, granulocytes, lymphocytes and monocytes. Adjusted odds ratio, [OR] for 99th percentile was 1.37 (95% confidence interval [CI], 0.73–2.56), 1.48 (95% CI, 0.79–2.77), 1.20 (95% CI, 0.63–2.31) and 1.88 (95% CI, 1.02–3.46), for total white cells, granulocytes lymphocytes and monocytes, respectively, compared to the reference percentile (5th-95th) (Table 2). We also analysed the effect of high leukocyte counts on VT in high risk groups, including surgical patients, hospitalized patients, and patients with cancer. Adjusted OR for high leukocyte counts (white cell, lymphocyte, monocyte or granulocyte counts 〉 97.5th percentile) was 6.3 (95% CI, 0.84–47.1) for groups who had surgery or were hospitalized and 2.2 (95% CI, 0.6–8.2) for patients with cancer, respectively, compared with cell counts within the percentile between 5th and 97.5th. Conclusions: High blood leukocyte count is associated with increased risk of VT. The risk is further increased in high risk groups. These results may assist in individually tailored thromboprophylaxis in high risk groups. Disclosures: No relevant conflicts of interest to declare.

Description: Risk factors for deep-vein thrombosis have been shown not to be always the same as for pulmonary embolism. A well-known example is the factor V Leiden (FVL) paradox: the FVL mutation poses a clearly higher risk for deep-vein thrombosis (DVT) than for pulmonary embolism. We aimed to expand this paradox and therefore present risk estimates for several established risk factors for DVT and pulmonary embolism separately. When such separate risk estimates could not be retrieved from the literature, we calculated these risks in our own data, a large population-based case-control study on venous thrombosis (the MEGA study). Our results showed that the FVL paradox can be broadened (ie, the risk factors oral contraceptive use, pregnancy, puerperium, minor leg injuries, and obesity have an effect comparable with FVL). Furthermore, we found that pulmonary conditions, such as chronic obstructive pulmonary disease, pneumonia, and sickle cell disease, were risk factors with an opposite effect: a higher risk of pulmonary embolism, but little or no effect on DVT. These findings suggest that pulmonary embolism and DVT may not always have the same etiology, and encourage unraveling this phenomenon in further studies.

Description: Abstract 3393 Background: Ethnic differences in the incidence of venous thrombosis have been appreciated for many years. However, with few exceptions, most of the studies on this subject were based on administrative databases from North America and China. The aim of this study was to investigate the risk of venous thrombosis in different first and second generation immigrant groups included in a large population-based case-control study, performed in the Netherlands. Methods: This study was performed using data from the MEGA study (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis-study), a large, population based case-control study on risk factors for venous thrombosis from the Netherlands. Inclusion criteria consisted of patients and controls whom information were available on the country of birth. For the analysis related to immigration background, patients were compared with random digit dialing (RDD) controls. First generation immigrants were classified as those who were born outside the Netherlands. Second generation immigrants were similarly defined as first generation immigrants, except that second immigrants were born in the Netherlands, while both parents were born in one of aforementioned other countries. In total, 6899 participants were included, of whom 4300 patients and 2599 RDD controls. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated as estimates of the relative risk, and were adjusted for age, sex, body mass index, smoking, hormonal factors, alcohol consumption, physical activity and malignancy by unconditional logistic regression. Results: The risk of venous thrombosis varied according to the region of birth (Table 1). When compared with the Dutch, Eastern Europeans reached the highest and East/Southeast Asians the lowest risk of venous thrombosis with OR of 2.35, (95% CI, 1.09–4.59) and 0.44 (95% CI, 0.29–0.68), respectively after multivariate adjustments. Caribeans showed an intermediate lower risk of 0.69 (95% CI, 0.36–1.30) after multivariate adjustments (Table 1). We did not observe a major difference on the risk for VT between first and second generation immigrants, although the number of second generation immigrants was small for some groups. Subgroup analysis did not show major differences according to immigration groups, except for Eastern Europeans, who had a higher risk for unprovoked event with OR of 3.79 (95% CI, 1.44–9.97) and East/Southeast Asians with higher risk for pulmonary embolism with OR of 0.60 (95% CI, 0.36–1.0) (Table 2). In comparison with Dutch controls, East/Southeast Asians controls had lower prevalence of factor V Leiden (6% and 1%, respectively) and prothrombin mutation (2% and 1%, respectively) but higher blood group non-O (54% and 62%, respectively). Risk of VT in East/Southeast Asians adjusted for age, sex, factor V Leiden and blood group non-O was 0.53 (95% CI, 0.35–0.80). Analysis of a panel of procoagulant, anticoagulant, profibrinolytic and genetic factors are underway and is expected to be available before the ASH conference of 2012. Conclusions: The risk of VT varies in different populations. The risk of VT in East/Southeast Asians was the lowest and was virtually unchanged after adjustment for several environmental and genetic known risk factors for VT. Disclosures: No relevant conflicts of interest to declare.

Description: Vitamin K antagonists (VKAs) are effective antithrombotic agents and advocated in guidelines for the management of cardiovascular disease. However, in the trials underlying these guidelines, many patients were excluded. We performed a case-control study in 993 patients receiving VKAs, who required hospitalization for bleeding, and contrasted them to 993 matched control patients on VKAs, who were hospitalized for an infection. We analyzed whether patients and controls would have been eligible for the clinical trials on which their indication for anticoagulation was based, and estimated the risk of hemorrhage associated with exclusion criteria as applied in those trials. Approximately one quarter (23% [95% CI: 21%-26%]) of controls had one or more exclusion criteria for the trials, supporting the use of anticoagulation for their condition. Forty percent of patients presenting with bleeding had one or more exclusion criteria (95% CI: 37%-43%). Having one exclusion criterion resulted in a 2.9-fold increased risk of bleeding (95% CI: 2.2-3.9), and this risk increased sharply when more than one exclusion criterion was present. VKAs are often prescribed to patients who would not have qualified for clinical trials, and in these patients a careful consideration should be made regarding the expected efficacy and the risk of bleeding.

Description: Abstract 2245 Background: It was in 2003 first reported that atherosclerosis was twice as prevalent in patients with unprovoked venous thrombosis as compared with age and sex matched controls. However, two subsequent population based prospective cohort studies failed to confirm this association. In the latter two study designs, atherosclerosis measurements were only registered at baseline, and it could have taken years before venous thrombotic events occurred. Such a time window may have nullified the outcomes of these two studies. In the Tromsø Study, a population based prospective cohort study from Norway, all participants aged 55–74 years and a random 5–10% sample in the other age groups 〉 24 years, were invited to ultrasound scanning for atherosclerosis assessment at enrollment in 1994–1995 (total n=6651). Atherosclerosis measurements were repeatedly performed in 2001 and 2007, also after a venous thrombotic event occurred. Study aims: 1) To test whether the presence of atherosclerosis, based on time dependent measurements, increases the risk of venous thrombosis, while taking confounding or modifying factors such as lipid lowering drugs into close account, and 2) whether venous thrombosis increases the risk of atherosclerosis either directly or through confounding or modifying factors. Methods: Carotid intima media thickness (IMT) and total plaque area (TPA) was assessed by ultrasound examination of the right carotid artery. All venous thrombotic events were identified between date of enrollment to December 31, 2010 (n=303). For the statistical analysis for the study question: “Does the presence of atherosclerosis increase the risk of venous thrombosis?”, we analyzed the Tromsø cohort with an extended Cox model, with IMT or TPA as a time-dependent covariate. This analysis was adjusted for age, sex, body mass index (BMI), smoking and use of lipid lowering drugs. For the statistical analysis of the study question: “Does venous thrombosis increase the risk of atherosclerosis?”, we applied a multiple linear regression model in which we compared participants that had venous thrombosis with participants that did not have venous thrombosis during follow-up. Results: Crude analyses showed that the risk of venous thrombosis increased across quartiles of IMT, which became more apparent when IMT was entered in the model as a time dependent covariate. As compared with participants in the lowest quartile, hazard ratios were 2.01 (95% CI, 1.21–3.36), 2.21 (95% CI, 1.34–3.64) and 3.11 (95% CI, 1.93–4.99), for increasing quartiles of IMT, respectively. As with IMT, there was a dose response relation between increasing levels of TPA and venous thrombosis risk when TPA was entered in the model as a time dependent covariate. However, the associations diminished after adjustment for age, sex, BMI and smoking. Adjusted hazard ratios were, again, slightly higher when IMT or TPA outcomes were entered in the model as time dependent covariates as compared with the crude models, with relative risks of 1 (reference), 1.20 (95% CI, 0.70–2.06), 1.24 (95% CI, 0,71–2.16) and 1.50 (95% CI, 0.85–2.62) for the increasing IMT quartiles, respectively. Risk estimates were not materially affected by provoked or unprovoked venous thrombotic event type. Further adjustments for use of lipid lowering drugs did not significantly affect the associations between IMT and venous thrombosis, or TPA and venous thrombosis, respectively. Next, we analyzed if atherosclerosis progression was affected by venous thrombosis onset. We observed a steadily increase of both IMT and TPA levels through time in participants without venous thrombosis (IMT 0.861 mm at baseline and 0.979 mm at second follow-up). However, these increases were comparable to increases in IMT/TPA levels in participants that did develop venous thrombosis, after adjustments for age, sex, BMI, smoking and use of lipid-lowering drugs (IMT mean difference 0.002 mm; 95% CI −0.019 to 0.023 at baseline, and −0.011; 95% CI, −0.056 to 0.033 at second follow-up). Timing of venous thrombotic event onset did also not reveal a relationship with atherosclerosis progression. Conclusion: The presence of atherosclerosis, based on time dependent IMT or TPA measurements, was not a risk factor for venous thrombosis in this study. Furthermore, patients with a venous thrombotic event did not experience increased atherosclerosis progression over time compared to subjects without venous thrombosis. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3985 Poster Board III-921 Background Venous thrombosis has genetic and acquired risk factors, and it has been proposed that several risk factors are needed for the occurrence of the disease. The identification of common gene variants associated with venous thrombosis may improve the ability to predict the risk and understanding of this disease. In a recent study, we aimed to identify genetic variants that are associated with deep vein thrombosis in individuals aged younger than 70 years (JAMA 2008; 299:1306-14). Of nearly 20000 single nucleotide polymorphisms (SNPs) that were genotyped, 7 SNPs were associated with deep vein thrombosis (range odds ratios, 1.1-1.3). However, studies of thousands of SNPs can lead to false-positive associations. Replication studies are therefore pivotal to account for false-positive associations. Objective To assess the risk of venous thrombosis of aforementioned SNPs in a large population based study. Methods From the residents of Nord-Trøndelag county in Norway aged 20 years and older (n = 94194), we identified all patients with an objectively verified diagnosis of venous thrombosis that occurred between 1995 and 2001. By this date we had registered 515 patients with a first venous thrombosis; an age- and sex-stratified random sample of 1476 controls without previous venous thrombosis was drawn from the original cohort. Patients and diagnosis characteristics were retrieved from medical records. Of the 7 SNPs that were associated with deep vein thrombosis in our previous study, 6 were analyzed in the present study, i.e. rs13146272 in CYP4V2; rs2227589 in SERPINC1; rs1613662 in GP6; rs670659 in RGS7; rs1523127 in NR1I2; and rs6048 in F9. DNA concentrations were standardized to 10 ng/μL using PicoGreen (Molecular Probes, Invitrogen Corp, Carlsbad, CA, USA) fluorescent dye. Genotyping of individual DNA samples were demonstrated by polymerase chain reactions using the TaqMan assay. The technicians were blinded to whether the samples came from patients or control subjects. Results The median age of both cases and controls at baseline was 70 years (range, 20-98). Almost half of patients and controls were men. Two thirds of the patients had deep vein thrombosis and one third had pulmonary embolism. Among the 515 events, 246 were idiopathic (48%). The prevalences of the 6 analyzed risk alleles were 17-96% in the patients and 16-96% in the control group. Only the F9 (rs6048) risk allele in men was consistently associated with an increased risk of venous thrombosis with odds ratios of 1.27 (95% CI, 0.83-1.93) for deep vein thrombosis, 1.62 (95% CI, 0.91-2.89) for pulmonary embolism, and 1.38 (95% CI, 0.97-1.97) for total venous thrombosis. For all other risk alleles we found odds ratios for venous thrombosis close to 1.0 compared to their reference allele. Odds ratios for provoked or idiopathic venous thrombosis again showed that only the F9 risk allele in men was consistently associated with an increased risk with an odds ratio of 1.30 (95% CI, 0.82-2.08) for provoked venous thrombosis and 1.47 (95% CI, 0.90-2.38) for idiopathic venous thrombosis, respectively, compared to men with the G allele. To make the current analysis more similar with our previous study, we restricted the analysis to those who were younger than 70 years. This resulted in slightly higher odds ratios for venous thrombosis in CYP4V2, SERPINC1 and GP6 variants (Table). Conclusion This population based study confirmed the previous finding that men with the A allele of rs6048 in F9 have an increased risk of venous thrombosis, while we could not replicate the association of gene variants in CYP4V2, SERPINC1, GP6, RGS7 and NR1I2 with venous thrombosis, possibly excepted for CYP4V2, SERPINC1 and GP6 gene variants in individuals aged younger than 70 years. Disclosures: No relevant conflicts of interest to declare.