Unprovoked Venous Thromboembolism Patients Research Articles

Poor patients' knowledge about venous thromboembolism and its therapy is associated with increased risk of major bleeding and discontinuation of anticoagulation: A cohort study.

It has been shown that patients' knowledge about venous thromboembolism (VTE) and its therapy is suboptimal, which might reduce compliance and worsen prognosis. We investigated whether low VTE patients' knowledge affects their clinical outcomes during long-term follow-up. We evaluated 151 consecutive patients (51.8 ± 15.7 years) after unprovoked VTE, who were recruited from the outpatient clinic (Krakow, Poland). All patients received anticoagulant treatment, mostly with direct oral anticoagulants (n = 113, 74.8%). The modified Jessa Atrial fibrillation Knowledge Questionnaire (JAKQ-VTE; 16 questions) was used to assess the knowledge of VTE and anticoagulant therapy. During a median follow-up of 58.0 months, VTE recurrence, major bleeding, and anticoagulation withdrawal were recorded. The median percentage of correct responses was 62.5% (12.5-100%) and was inversely correlated with age (P < .01). Diabetic patients and those with positive family history of VTE had lower overall scoring compared to the remainder (both P < .05). Major bleeding (n = 10, 6.6%) and anticoagulation withdrawal (n = 28, 18.5%), but not VTE recurrence (n = 12, 7.9%), were associated with lower overall scoring compared to the remainder (48.8% ± 12.5% vs 63.8% ± 16.3%, P = .003 and 55.3% ± 14.7% vs 64.4% ± 16.3%, P = .040, respectively). Major bleeding was independently associated with the female sex (hazard ratio [HR] 6.18; 95% confidence interval [CI] 1.15-33.19, P = .034), younger age (HR per 10 years 0.55; 95% CI 0.34-0.90, P = .016), OAC therapy discontinuation (HR 6.69; 95% CI 1.62-27.70), and lower overall scoring of JAKQ-VTE (HR 0.60 per 10 percentage points; 95% CI 0.40-0.92, P = .019). Insufficient knowledge about VTE and anticoagulant treatment predisposes to a higher risk of major bleeding and therapy discontinuation, but not VTE recurrence in unprovoked VTE patients during long-term follow-up.

Small RNA Sequencing Reveals Exosomal miRNAs as Unique Feature Markers in Unprovoked Venous Thromboembolism

Introduction: Venous thromboembolism (VTE) is a common cardiovascular disease. MicroRNAs (miRNAs) play a key role in VTE; however, the role of exosomal miRNAs in VTE remains unknown. Therefore, we aimed to identify key exosomal miRNAs and their potential mechanisms in VTE. Methods: We collected 31 samples from unprovoked VTE patients and 25 samples from healthy individuals. Exosomal miRNA sequencing was performed on 11 unprovoked VTE samples and 9 normal samples, and the remaining samples were used to verify the expression level of candidate 9 miRNAs in VTE and normal samples. The sequencing data were used to analyze exosomal miRNA expression. Meanwhile, gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to determine the potential biological functions of differentially expressed miRNA target genes. Results: A total of 32 differentially expressed miRNAs were identified by sequencing. Among the 32 miRNAs, 23 miRNAs were upregulated (72%), and 9 miRNAs were downregulated (28%). In addition, we found that the biological functions and metabolic pathways of the target genes were related to hemostatic factors involved in VTE, indicating the regulation of differentially expressed miRNAs. We identified key miRNAs by constructing a miRNA-messenger RNA regulatory network and found that the target genes were related to VTE. We finally determined that the abnormal expression of 9 miRNAs is closely related to VTE, and the expression level between VTE and normal was verified through other samples. Conclusion: Our study identified a set of key miRNAs for future research on the molecular mechanisms of VTE.

A Decision Model to Estimate Risk Thresholds for Guiding Duration of Anticaogulation in Unprovoked Venous Thromboembolism

▪Background: For patients with a first unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulant therapy (AT) is a crucial clinical dilemma which has yet to be resolved . Choosing short-term (3-6 months) or indefinite AT, requires balancing the long-term risk of recurrent VTE when AT is discontinued, with the long-term risk of major bleeding (MB) from extended AT. Current guidelines suggest considering indefinite AT in all unprovoked VTE patients with non-high bleeding risk. This however, is a weak-evidence recommendation based on limited data, and no precise risk thresholds have been established to help guide treatment duration in this patient population. From an economic perspective, we aimed to identify thresholds of the risk of MB and recurrent VTE for which indefinite AT, as compared to stopping AT after initial short-term treatment, may be warranted.Methods: We constructed a Markov decision model of patients with a first unprovoked VTE who had completed at least 3-6 months of initial AT. The model adopted a lifetime horizon and a publicly-funded healthcare system perspective. Using a cycle length of one year, the model tracked recurrent VTE (DVT and/or PE), MB, and death from any cause [Figure 1]. For the base case, we considered patients aged 57 years, having a life expectancy of 30 years, annual risk of MB on Vitamin K Antagonists of 1.5%, annual recurrent VTE risk of 5% per year off therapy, case-fatality-rate (CFR) for MB of 11.3%, and CFR for recurrent VTE of 3.6%. We expressed our results as Incremental Net Benefit (INB) which incorporates costs, life-expectancy, quality-adjusted life-years (QALYs), and a willingness to pay (WTP) value. INB is the incremental benefit, expressed in monetary terms ($), of offering a patient treatment (indefinite AT) rather than the comparator (stopping AT). An INB > 0 favours the treatment, whereas an INB < 0 favours the comparator.Results: For the base case analysis with assuming a decision-maker's WTP threshold of $50,000/QALY, indefinite AT was not justified (i.e. INB < 0) when the annual risk of recurrent VTE off therapy was less than 7.1% [Figure 2], or when the annual risk of MB exceeded 2.4% [Figure 3]. Furthermore, in a two-way sensitivity analysis [Figure 4], as the MB risk increased, so did the recurrent VTE risk threshold for which indefinite AT would be warranted. As illustrated through three hypothetical situations outlined in Figure 4; for a patient with an annual MB risk of 3.5% [scenario A], a recurrence risk of >15% would be required for indefinite AT to be favorable (i.e. INB > 0). Similarly, using a base case annual MB risk of 1.5% [scenario B], from an economic standpoint, the decision to offer indefinite AT would not be preferred for a patient in whom the risk of recurrence is 3%, but may be supported for a patient in whom the risk of recurrence is 10%. Lastly, for a patient with an annual recurrent VTE risk of < 1% [scenario C], continuing AT indefinitely would never be justified, irrespective of the risk of MB.Conclusions/Implications: To the best of our knowledge, this is the first decision analysis of a hypothetical cohort of unprovoked VTE patients that identifies risk thresholds of MB and recurrent VTE to guide treatment duration. From an economic viewpoint, our analysis demonstrates that choosing indefinite AT in such patients may not be justified at the proposed risk thresholds. Furthermore, long-term follow up demonstrates that VTE recurs in less than 50% of such patients after stopping AT;thus, considering indefinite AT in all unprovoked VTE patients is an inefficient use of resources, and exposes a large proportion of patients to the unnecessary risks, burdens and costs of lifelong AT. Establishing risk thresholds, as achieved through our decision model, allows individualized treatment and helps guide patient-centered decision making. If validated and further optimized (as planned prior to the ASH), findings from our study could change clinical practice. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Genetic Risk Profiling Associated with Recurrent Unprovoked Venous Thromboembolism.

Introduction: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and/or pulmonary embolism (PE), is a common, acute, multifactorial disease with a five-years cumulative incidence of recurrence of approximately 25%. Actually, no single genetic defect can predict the risk of recurrence of VTE. Therefore, individual genetic risk profiling could be useful for the prediction of VTE recurrence. Aim of the study: To assess the combined effect of the common prothrombotic genotypes on the risk of recurrence of VTE in recently diagnosed unprovoked VTE patients. Patients and methods: This population based, prospective follow-up study was carried out from January 2015 to December 2020 in (internal medicine, cardiovascular medicine and anesthesia and ICU departments, Tanta University Hospital, Egypt) on 224 recently diagnosed unprovoked VTE patients. Whole blood was collected by standard venipuncture at the time of admission prior to the beginning of anticoagulant therapy. Genomic DNA was extracted and was genotyped for the 5-SNPs Genetic risk score (GRS), previously validated for first venous thrombosis (FVL rs6025, PTM rs1799963, ABO rs8176719, FGG rs2066865 and FXI rs2036914). Results: The main important finding in the present study was that patients having ≥3 risk alleles were associated with higher risk of VTE recurrence compared to those having ≤2 risk alleles (the reference group) (HR 2.5, 95% CI 1.48–4.21) (p = 0.001). Patients with GRS ≥ 3 had a significantly shorter time recurrence free survival (43.07 months) compared to the low risk group of patients with GRS (0–2) (p < 0.001). Conclusion: GRS model could be an effective and useful model in risk stratification of VTE patients, and genetic risk profiling of VTE patients could be used for the prediction of recurrence of VTE.

Homozygous methylentetrahydrofolate reductase C667T genotype anticipates age at venous thromboembolism by one decade.

The aim of the study was to compare age at first venous thromboembolism (VTE), plasma homocysteine and activated partial thromboplastin time ratio (aPTTr) amongst unprovoked VTE patients with the methylentetrahydrofolate reductase (MTHFR) C667T genotypes, and to identify predictors of age at first VTE, of plasma homocysteine and of the aPTTr; to evaluate whether heterozygous or homozygous prothrombin (PT) G20210A mutation lowered the age at first VTE when associated with MTHFR TT. Retrospective cohort study on 259 MTHFR TT, 76 MTHFR TC and 64 MTHFR CC participants with unprovoked VTE; each participant contributed age, sex, age at VTE, history of dyslipidaemia, hypertension, smoking, homocysteine (measured by enzyme immunoassay) and aPTTr (measured by standard coagulation assay). Age at first VTE was lower in MTHFR TT than MTHFR TC and CC (41 ± 14 vs. 50 ± 16 vs. 51 ± 12 years, respectively, P < 0.0001); plasma homocysteine was higher in MTHFR TT than in the other groups (22 ± 21 vs. 12 ± 11.6 vs. 10 ± 3.3 μmol/l, respectively, P = 0.0005) whilst aPTTr was not different. MTHFR TT independently predicted age at first VTE (P = 0.001), plasma homocysteine (P < 0.0001) alongside sex (P = 0.0007), age and smoking (P = 0.03 for both). Compound MTHFR TT with PT GA or AA had no lowering effect on age at first VTE compared with MTHFR TT alone (41 ± 13 vs. 41 ± 14 years). Plasma homocysteine inversely related to aPTTr in the MTHFR TT group (P = 0.003). MTHFR TT anticipates age at first VTE by an average of 10 years compared with MTHFR TC and CC genotypes.

Risk prediction of recurrent venous thromboembolism: a multiple genetic risk model

A single genetic biomarker is unable to accurately predict the risk for venous thromboembolism (VTE) recurrence. We aimed to: (a) develop a multiple single nucleotide polymorphisms (SNPs) model to predict the risk of VTE recurrence and (b) validate a previously described genetic risk score (GRS) and compare its performance with the model developed in this study. Twenty-two SNPs, including established and putative SNPs associated with VTE risk, were genotyped in the Malmö thrombophilia study cohort (MATS; n = 1465, follow-up ~ 10 years) by using TaqMan PCR. Out of 22-SNPs, 12 had an association with the risk of VTE recurrence and were included for calculating GRSs. The risk of VTE recurrence was calculated by stratifying patients according to number of risk alleles. In 12-SNP GRS, patients with ≥ 7 risk alleles were associated with higher risk of VTE recurrence compared to patients having ≤ 6 risk alleles. In a simplified model (8-SNP GRS), the discriminative power of 8-SNP GRS was similar to that of 12-SNP GRS based on post-test probabilities (PP). Furthermore, 8-SNP GRS further improved the risk prediction of VTE recurrence in unprovoked VTE and male patients (PP% = 15.4 vs 8.3, 17.1 vs 7.2 and 19.0 vs 7.1 for high risk groups vs low risk groups in whole population, males and unprovoked VTE patients respectively). In addition, we also validated previously described 5-SNP GRS in our cohort and found that the 8-SNP GRS performed better than the 5-SNP GRS in terms of higher PP. Our results show that a multiple SNP GRS consisting of 8-SNPs may be an effective model for prediction of VTE recurrence, particularly in unprovoked VTE and male patients.

10. Abstract Title: Long-term risk factors for occult cancer detection in patients with unprovoked venous thromboembolism: A post-hoc analysis of the REVERSE Study

Background: The diagnosis of an unprovoked (i.e., in the absence of any risk factors) venous thromboembolism (VTE) may be a sign of an underlying cancer. Previous estimates of the incidence rate of occult cancer in patients with unprovoked VTE are as high as 5-10%. However, screening methods to detect cancer early in these patients are of limited clinical value and previous identification of risk factors focused on short-term cancer diagnosis. Therefore, this study will assess the long-term incidence and risk factors of cancer in unprovoked VTE patients.

Effect of occult cancer screening on mortality in patients with unprovoked venous thromboembolism

IntroductionUnprovoked venous thromboembolism (VTE) may be the first manifestation of an underlying cancer. We aimed to determine whether extensive screening for occult cancer in patients with unprovoked VTE was effective in reducing overall mortality among VTE patients included in prospective cancer screening studies. MethodsThis pre-specified analysis of a systematic review and individual patient data meta-analysis included prospective studies comparing extensive screening with limited screening strategies for detection of occult malignant disease in unprovoked VTE patients. Overall mortality was calculated and compared according to the allocated screening strategies. ResultsAmong 1830 included patients, occult cancer was detected either at screening or during a 2-year follow-up period in 98 (5.4%, 95% CI 4.4 to 6.5). Twenty-seven out of the 56 patients (48.2%) diagnosed with cancer in the extensive screening group died during follow-up as compared with 23 out of 42 patients (54.8%) in the limited screening group (HR, 0.83; 95% CI, 0.48–1.45). Subgroup analyses according to time of cancer diagnosis (i.e. at screening vs. during follow-up) and according to whether cancer was diagnosed by limited screening or more extensive testing yielded similar results. ConclusionIn this individual patient data meta-analysis of clinical trials on limited vs. extensive screening, extensive screening for occult malignancy in patients with unprovoked VTE was not effective in reducing overall mortality. Diagnosing an occult cancer in unprovoked VTE patients was associated with a poor outcome.

Economic evaluation of strategies for restarting anticoagulation therapy after a first event of unprovoked venous thromboembolism

Background Following at least 3 months of anticoagulation therapy after a first unprovoked venous thromboembolism (VTE), there is uncertainty about the duration of therapy. Further anticoagulation therapy reduces the risk of having a potentially fatal recurrent VTE but at the expense of a higher risk of bleeding, which can also be fatal. Objective An economic evaluation sought to estimate the long-term cost-effectiveness of using a decision rule for restarting anticoagulation therapy vs. no extension of therapy in patients based on their risk of a further unprovoked VTE. Methods A Markov patient-level simulation model was developed, which adopted a lifetime time horizon with monthly time cycles and was from a UK National Health Service (NHS)/Personal Social Services (PSS) perspective. Results Base-case model results suggest that treating patients with a predicted 1 year VTE risk of 17.5% or higher may be cost-effective if decision makers are willing to pay up to £20 000 per quality adjusted life year (QALY) gained. However, probabilistic sensitivity analysis shows that the model was highly sensitive to overall parameter uncertainty and caution is warranted in selecting the optimal decision rule on cost-effectiveness grounds. Univariate sensitivity analyses indicate variables such as anticoagulation therapy disutility and mortality risks were very influential in driving model results. Conclusion This represents the first economic model to consider the use of a decision rule for restarting therapy for unprovoked VTE patients. Better data are required to predict long-term bleeding risks during therapy in this patient group.

Extensive screening for occult malignancy in unprovoked venous thromboembolism: A meta-analysis

BackgroundThe present meta-analysis aimed to evaluate the efficacy and sensitivity of an extensive screening strategy for occult malignant diseases in patients with unprovoked venous thromboembolism (VTE). MethodsWe conducted a systematic search of PubMed, Cochrane, EMBASE, and relevant article references. Meta-analysis was used to pool weighted relative risks (RR) for the rate of missed diagnosis, all-cause mortality, and cancer-related mortality. Heterogeneity test was performed using the inconsistency index. Furthermore, pooled analysis of the sensitivity and the proportion of false-positive findings of PET/CT were conducted. ResultsA total of 5 controlled studies were included with 1,115 and 1,159 unprovoked VTE patients receiving limited or extensive screening strategy, respectively. The risk of missed diagnosis (RR, 0.51; 95% CI, 0.20–1.28; P=0.15) was not significantly different between the limited and extensive screening group. Moreover, there was no statistically significant difference in all-cause mortality (RR, 0.86; 95% CI, 0.58–1.27; P=0.44) and cancer-related mortality (RR, 0.86; 95% CI, 0.46–1.62; P=0.65) between the two groups. The pooled sensitivity and proportion of false-positive findings of PET/CT as a screening tool for occult malignancy in patients with unprovoked VTE was 95% (95% CI, 38%–100%) and 33% (95% CI, 20%–47%), respectively. ConclusionsExtensive screening strategy did not show a clinically significant benefit over limited screening strategy. Considering the high cost and the additional physical and emotional harm, current evidence did not support extensive screening for each patient in the setting.

Association between TLR9 rs5743836 polymorphism and risk of recurrent venous thromboembolism

Recent gene knockout studies on mice have shown the role of toll-like receptor 9 (TLR9) in resolution of venous thromboembolism (VTE) through sterile inflammation. However, the role of a putative functional TLR9 polymorphism (rs5743836) in risk assessment of VTE recurrence remains unknown. The aim of our study was to investigate the TLR9 rs5743836 polymorphism in VTE patients and its association with the risk of VTE recurrence. We analyzed TLR9 rs5743836 polymorphism in Malmö thrombophilia study patients; a prospective follow-up study of 1465 VTE patients by Taqman PCR. From a total of 1465 VTE patients, those who had VTE before inclusion and those who died or had VTE recurrence during anticoagulant treatment were excluded (n = 415). Cox regression analyses were performed on the remaining 1050 VTE patients, including 126 (12.5%) patients that had recurrent VTE during follow-up period. TLR9 polymorphism was significantly associated with higher risk of VTE recurrence in female patients (HR 3.46, 95% CI 1.06–11.33) independent of acquired risk factors for VTE, family history, risk of thrombophilia and deep vein thrombosis (DVT) location. Similarly, in unprovoked VTE patients, TLR9 polymorphism was significantly associated with higher risk of VTE recurrence in female patients (HR 5.94, 95% CI 1.25–28.13) after adjusting for family history, risk of thrombophilia and DVT location. No association between TLR9 polymorphism and risk of VTE recurrence was found in male patients. Our results suggest that TLR9 rs5743836 polymorphism is an independent risk factor for VTE recurrence in female patients but not in males.

D-dimer levels and recurrence in patients with unprovoked VTE and a negative qualitative D-dimer test after treatment

BackgroundThe rate of recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who had a negative qualitative D-dimer test one month after stopping anticoagulant therapy was higher than expected in the D-dimer Optimal Duration Study (DODS). ObjectivesTo determine whether quantitative D-dimer levels using a low threshold, age- and sex-specific thresholds, or repeated measurements, would improve identification of patients at low risk of recurrent VTE. Materials and methodsD-dimer levels were quantified in banked samples from 307 patients in DODS who had a negative qualitative D-dimer test while on, and 1month after stopping, anticoagulant therapy and the rates of recurrent VTE were determined in patients with D-dimer levels below various predefined thresholds. ResultsThe rate (per patient year) of recurrent VTE was: 5.9% with D-dimer levels<250μg/l at one month; 5.2% with D-dimer levels between 250 and 499μg/l at one month; 5.0% with D-dimer levels less than predefined age- and sex-specific thresholds at one month; and 6.3% when D-dimer levels were <500μg/l at both one and 7months after stopping anticoagulant therapy. These rates are similar to the overall event rate of 6.3% in patients who stopped treatment. ConclusionsAmong unprovoked VTE patients who had a negative qualitative D-dimer test during and after anticoagulant therapy, low D-dimer thresholds, age and sex-adjusted thresholds or repeated measurements, did not identify subgroups with a very low rate of recurrence.

Red Cell Distribution Width Has a Predictable Value for Differentiation of Provoked and Unprovoked Venous Thromboembolism.

Venous thromboembolism (VTE) is generally classified as provoked or unprovoked. This dichotomy is important for following patients, mortality rate, prognosis and whether more efficient therapy is needed. In VTE patients, during initial diagnosis, it is not known exactly whether red cell distribution width (RDW) have a predictable value for this differentiation and pathogenesis. In this study, 298 patients with VTE and 197 control subjects were included. Patients with VTE were defined as provoked or unprovoked with respect to physical examination findings and laboratory values. Changes in RDW were tested between VTE patients and control subjects, provoked and unprovoked VTE patients, and separately with control subjects. RDW was found to be high in provoked and unprovoked groups compared with control group (p<0.001, p=0.003 respectively). RDW was significantly high in provoked VTE patients group compared with unprovoked patients (p<0.001) and a cut-off value was found to be 13.6%. In ROC analysis, sensitivity was 90.19% and specificity was 82% (95% CI 85.4-93. 8% and 95% CI 72.3-89. 6% respectively). RDW could be used as a simple, costeffective and a reliable test independent of age in differentiation of provoked and unprovoked VTE. In order to better understand its role, prospective large homogenized population studies in different regions are necessary.

Retrospective Cohort of Unprovoked Venous Thromboembolism Patients: What Proportion Have Potent Thrombophilias Necessitating Indefinite Anticoagulants?

Introduction Thrombophilia testing in unprovoked venous thromboembolism patients (VTE) is controversial. Common thrombophilias such as Factor V Leiden or prothrombin gene variant appear to not importantly increase the risk of VTE recurrence, and thus are not considered in anticoagulation management decisions. However, patients with potent thrombophilias such as antiphospholipid antibodies (APLA), antithrombin deficiency, protein C and S deficiency, and homozygous genetic thrombophilias or combined defects are at higher risk of recurrence and it is recommended that they receive long-term anticoagulation. If the proportion of patients with "potent" thrombophilia is high then thrombophilia testing should be conducted. We sought to determine the proportion of unprovoked VTE patients with "potent" thrombophilia. Methods All patients with managed in our oral anticoagulation management system in the period from 1998 to 2015 were potentially eligible for the study. Inclusion criteria were: 1) symptomatic, objectively confirmed VTE unprovoked proximal deep vein thrombosis or pulmonary embolism. Exclusion criteria were: 1) cancer or myeloproliferative disease at the time of VTE diagnosis; 2) no cast, surgery, trauma or immobilization (&gt;3 days in bed 90% of waking hours) in the 90 days prior to diagnosis. We selected unprovoked VTE patients diagnosed between 2002 and 2010, as thrombophilia testing was relatively universal and available in our electronic system in that time frame (N=1344). We then selected a convenience sample of N=1165. The primary outcome measure was the proportion of patients with "potent" thrombophilia (potent= homozygous Factor V Leiden, homozygous Prothrombin gene variant, APLA, protein C, protein S or anti-thrombin deficiency or combined deficiencies). Results In 1165 patients with unprovoked VTE, complete screening was done in 470 patients (40.34%) and 976 (83.78%) had at least one thrombophilia test. Complete thrombophilia testing was defined as a screen including testing for factor V Leiden, prothrombin gene defect, APLA, anti-thrombin deficiency, protein C, and protein S. Potent thrombophilias were demonstrated in 103/1165 patients (8.84%; 95% CI, 7.34 to 10.61) (Table 2) in the total study population, and 103/976 (10.55%; 95% CI, 9.62-14.47) in patients with at least one thrombophilia test. Conclusion The proportion of unprovoked VTE patients with "potent" thrombophilia is high. Given a high proportion of "potent' thrombophilia patients who likely benefit from indefinite anticoagulation, complete thrombophilia testing appears warranted in patients with unprovoked VTE in whom anticoagulants maybe discontinued. Thrombophilia testing is warranted for a selected group of patients to detect high-risk thrombophilias that could impact anticoagulation management. Table 1. Thrombophilia screening Complete screening 470 (40.3%) No screening 189 (16.2%) At least one thrombophilia test 976 (83.8%) Table 2. Thrombophilia All patients (n=1165) Tested for individual thrombophilia % 95% CI % 95% CI FVL Heterozygous 162/1165 (13.9%) 12.0-16.0% 162/883 (18.4%) 15.9-21.0% FVL Homozygous 4/1165 (0.3%) 0.1-0.9% 4/883 (0.5%) 0.2-1.2% Prothrombin Heterozygous 63/1165 (5.4%) 4.3-6.9% 63/831 (7.6%) 6.0-9.6% Prothrombin Homozygous 1/1165 (0.0%) 0.0-0.5% 1/831 (0.1%) 0.0-0.7% Antithrombin deficiency 10/1165 (0.9%) 0.5-1.6% 10/815 (1.2%) 0.7-2.2% Protein C deficiency 18/1165 (1.6%) 1.0-2.4% 18/639 (2.8%) 1.8-4.4% Protein S deficiency 13/1165 (1.1%) 0.7-1.9% 13/635 (2.1%) 1.2-3.5% Lupus anticoagulant 24/1165 (2.1%) 1.4-3.1% 24/849 (2.8%) 1.9-4.2% Anticardiolipin IgM 16/1165 (1.4%) 0.9-2.2% 16/886 (1.8%) 1.1-2.9% Anticardiolipin IgG 20/1165 (1.7%) 1.1-2.6% 20/885 (2.2%) 1.5-3.5% β-2 microglobulin IgM 10/1165 (0.9%) 0.5-1.6% 10/333 (3.0%) 1.6-5.4% β-2 microglobulin IgG 8/1165 (0.7%) 0.4-1.4% 8/333 (2.4%) 1.2-4.7% Homocysteine 50/1165 (5.7%) 4.3-7.4% 50/668 (7.5%) 5.7-9.7% Factor VIII elevated 11/1165 (0.9%) 0.5-1.7% 11/646 (1.7%) 1.0-3.0% At least one or more of the above 331/1165 (28.4%) 25.9-31.1% 331/976 (33.9%) 31.0-36.9% Potent thrombophilia 103/1165 (8.8%) 7.34-10.6% 103/976 (10.6%) 9.6-14.5% Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract 235: Impact of Short-term Anticoagulant Use on the Risk of Recurrent Venous Thromboembolism: Evidence From Insurance Claims in the United States

Background: Duration of oral anticoagulant therapy for venous thromboembolism (VTE) is debatable. Moreover, literature shows that approximately 12% of the VTE patients discontinue warfarin therapy within 3 months and 63% discontinue within 1 year. Aim: To assess the real world impact of short term use of anticoagulants on the risk of recurrent VTE in the United States. Methods: Retrospective analyses of a large national claims dataset from 01/01/2007 to 12/31/2011 were conducted. Adult patients who had at least 3 months of continuous anticoagulant use (vitamin K antagonist or low molecular weight heparin) following an incident VTE were selected. Time to recurrent VTE after anticoagulant discontinuation was assessed using Cox proportional hazard regressions, adjusting for baseline characteristics. Subgroup analyses were conducted in unprovoked VTE, provoked VTE, and VTE patients with cancer. Results: We identified 31,906 patients with incident VTE. Within 1 year after the incident VTE, therapy was discontinued among 75.4% of the patients, with an average of 6 months of treatment. Patients with treatment discontinuation were younger than those without (mean age: 57 vs. 60 years), more likely to be females (51% vs. 46%) and had more co-morbidities (all P&lt;0.05). The adjusted rate of recurrent VTE was 94% higher in patients with treatment discontinuation than in those without (hazard ratio [HR] = 1.9, 95% CI: 1.5-2.5). The higher rate of recurrent VTE associated with anticoagulant discontinuation was observed regardless of the timing of discontinuation (discontinued in 3-6, 6-9, or 9-12 months after incident VTE). The HR was found to be similar in the subgroups. Conclusion: Even after 3 months of anticoagulant treatment, the patients remained at high risk for recurrent VTE once the treatment was stopped by the physician or discontinued by the patient. Thus, longer-term use of anticoagulants may be warranted to prevent recurrent VTE.

Association between anticoagulant treatment duration and risk of venous thromboembolism recurrence and bleeding in clinical practice

IntroductionThis retrospective observational study examined whether anticoagulant treatment duration varies by risks of venous thromboembolism (VTE) recurrence and bleeding. Materials and methodsVTE patients naïve to anticoagulants were identified from the HealthCore Integrated Research Database between 06/01/2007 and 09/30/2011 and categorized into three groups: provoked, cancer-related, and unprovoked VTE. Treatment duration was from initiation to discontinuation of anticoagulation, based on a 60-day gap in prescription fill unless there was an international normalized ratio test every 42days. Bleeding risk was estimated using RIETE score, and VTE risk categories were based on ACCP guidelines. Kaplan-Meier curves and Cox proportional hazards models were used to evaluate association between VTE recurrence/bleeding and anticoagulation duration. ResultsOf 2002 patients identified (52.3% males, mean age 57±15years), 21.4% had provoked, 16.4% had cancer-related, and 62.1% had unprovoked VTE. Average anticoagulant treatment duration was 294±261days. After adjusting for demographics and clinical characteristics, provoked and cancer-related VTE patients were 32% (95% CI=14–54%, P<0.001) and 35% (95% CI=7–70%, P=0.013) more likely, respectively, to discontinue anticoagulants than unprovoked VTE patients. No differences were observed between provoked and cancer-related VTE patients. Patients with an intermediate/high bleeding risk were 26% (95% CI=14–36%, P<0.001) less likely to discontinue treatment than those with a low bleeding risk. ConclusionsThe observed anticoagulation duration for VTE may not be concordant with guidelines, due to the challenge of counterbalancing risks of VTE recurrence and bleeding. Further studies are needed to explore this.

Association Study of Microrna and Microrna-Biogenesis Gene Polymorphisms with Venous Thromboembolism (VTE) in Korean Population

AbstractAbstract 3395Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), represents a public health concern in Western and Asian countries. Venous thromboembolism often complicates the course of hospitalized patients but may also affect ambulatory and otherwise healthy people. The classic risk factors for VTE are cancer, surgery, prolonged immobilization, fracture, paralysis, oral contraceptive use, and hereditary coagulopathies. In addition to these classic risk factors, microparticle containing microRNA is a known risk factor for both arterial and venous thrombosis. The aim of study was to investigate genetic association between microRNAs or microRNA-biogenesis genes and VTE. We selected 6 well-studied polymorphisms of miR-146a (rs2910164), miR-196a2 (rs11614913), miR-499 (rs3746444), DICER (rs3742330), DROSHA (rs10719), and RAN (rs14035).Patients with consecutive VTE with recent (<6 months) objective diagnosis of DVT or PE, who visited to the CHA Bundang Medical Center (Seongnam, Korea) or Keimyung University hospital (Daegu, Korea) between May 2005 and December 2009, were enrolled in the study. We enrolled the patients with symptomatic VTE and excluded the patients with asymptomatic VTE. Venous thromboembolism was defined as provoked or unprovoked, depending on the presence or absence of any of the following risk factors: recent surgery (<3 months), recent trauma/fracture (<3 months), immobilization (>7 days), malignancy, stroke, severe medical disease, autoimmune disease, pregnancy, use of oral contraceptives, and known inherited thrombophilia. Venous thromboembolism was classified as provoked in the presence of at least one of these risk factors. The control group was selected among patients visiting the CHA Bundang Health Promotion Center for periodic health examinations, who had no medical history of VTE. The Institutional Review Board of CHA Bundang Medical Center approved the research protocol and written informed consent was obtained from all participating individuals. Genotyping of microRNA and microRNA-biogenesis gene polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Multivariate logistic regression was used to calculate strength of association.The genetic distributions of microRNA and microRNA-biogenesis gene polymorphisms were in Hardy-Weinberg equilibrium (Table 1). RAN rs14035 CC genotype was associated with increased VTE risk (adjusted odds ratio [AOR], 1.640; 95% confidence interval [CI], 1.106–2.432; P=0.014; Table 1). The statistical significance of RAN rs14035 CC was strengthened in unprovoked VTE patients (AOR, 2.478; 95% CI, 1.410–4.357; P=0.002; Table 2). Although other microRNA-related polymorphisms showed differences between controls and VTE patients, there were not positive statistical significances. In conclusion, RAN rs14035 CC may be a possible predisposing factor for VTE development. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Serum Lipoprotein (a) Levels in Patients with First Unprovoked Venous Thromboembolism is not Associated with Subsequent Risk of Recurrent VTE

Introduction Case-control studies suggest that elevated lipoprotein (a) (Lp(a)) is a risk factor for first venous thromboembolism (VTE). Lp(a) has not been prospectively investigated as a possible risk factor for recurrent VTE in first unprovoked VTE patients. We sought to determine if serum Lp(a) levels in patients with unprovoked VTE who discontinue anticoagulants after 5 to 7 months of therapy predict VTE recurrence in a prospective cohort study. Materials and Methods Serum Lp(a) measurements were obtained from 510 first unprovoked VTE patients treated for 5 -7 months with anticoagulants in a 12 center study. Patients were subsequently followed for a mean of 16.9 months (SD ± 11.2) for symptomatic VTE recurrence which was independently adjudicated with reference to baseline imaging. Results There was no significant association between Lp(a) as a continuous variable and recurrent VTE nor in gender stratified subgroups. No statistically significant differences were observed in the median Lp(a) concentrations between patients who recurred and those who did not recur (median (interquartile range): 0.09 g/L (0.17) versus 0.06 g/L (0.11) respectively; p = 0.15). The Lp(a) cut-off point of 0.3 g/L was not significantly associated with recurrent VTE for the overall population nor in gender stratified subgroups. Conclusions Elevated serum Lp(a) does not appear to be associated with recurrent VTE in patients with history of first unprovoked VTE and may not play a role in identifying patients with unprovoked VTE at high risk of recurrence. There was no optimal predictive threshold for the overall population or for sex sub-groups and Lp(a) ≥ 0.3 g/L was not a significant predictor of recurrent VTE.

Unprovoked Venous Thromboembolism: Short term or Indefinite Anticoagulation? Balancing Long-Term Risk and Benefit

Whether to continue oral anticoagulant therapy indefinitely after completing 3 to 6 months of oral anticoagulant therapy for “unprovoked” venous thromboembolism (VTE), is one of the most important unanswered questions in VTE management. This long-term decision should be based on balancing the long-term mortality risk from recurrent VTE, largely preventable with oral anticoagulant therapy, against the long-term mortality risk of major bleeding, the principle complication of oral anticoagulant therapy. There exist important knowledge gaps in estimating the long-term mortality risk of recurrent VTE in patients with unprovoked VTE who discontinue therapy and the long-term mortality risk from major bleeding in those who continue oral anticoagulant therapy. These knowledge gaps, reviewed herein, are the source of uncertainty for patients and health care providers wrestling with this important question. One promising solution is recurrent VTE risk stratification where unprovoked VTE patients are categorised as low or high risk for recurrent VTE and clinical decision making is less ambiguous and ultimately will likely lead to better outcomes.

Extended Follow-up of the Multi-Center Multi-National Prospective Cohort Study That Derived the “Men Continue and HERDOO2” Clinical Decision Rule Which Identifies Low Risk Patients Who May Be Able to Discontinue Oral Anticoagulants (Oac) 5-7 Months After Treatment for Unprovoked Venous Thromboembolism (VTE).

Abstract 451▪▪This icon denotes an abstract that is clinically relevant. Introduction:To continue or discontinue OAC after 6 months of therapy for VTE is one of the most important unanswered questions in VTE management. In 2007, we developed a clinical decision rule to identify low risk patients with unprovoked VTE who could safely discontinue OAC after 5-7 months of therapy. This clinical decision rule was developed from a large prospective cohort study of patients with unprovoked VTE who discontinued anticoagulants after 5-7 months of OAC and were subsequently followed for a mean of 18 months for recurrent VTE. The “MEN continue and HERDOO2” rule states that men and high risk women should continue anticoagulants indefinitely after unprovoked VTE. High risk women are women with ≥2 of the following 1)Hyperpigmentation, Edema or Redness (HER) on exam in either leg, 2)Vidas D-Dimer >250, 3)Obesity- BMI >30 or 4)Older age over 65. Given that the OAC treatment decision is a long-term treatment decision that needs to be counter-balanced with long-term bleeding risk from OAC (1-3% annual risk of major hemorrhage) it is important to determine long-term risks of recurrent VTE in unprovoked VTE patients, high risk patients and low risk patients. Objective:We sought to confirm that the risk of recurrent VTE in high risk patients remains elevated and conversely that the risk remains low in low risk women over longer term follow-up. Methods:Multi-centre prospective cohort study of first unprovoked VTE patients who had potential predictors collected while on OAC (including D-Dimer) enrolled from 2001 to March 2006. Patients were excluded if they had: 1) recurrent unprovoked VTE, 2) known high risk thrombophilia or 3) no consent. Symptomatic suspected VTE during subsequent follow-up (up to july 2009) off of OAC was investigated with reference to baseline imaging and then independently adjudicated. Results:646 participants were enrolled in 11 centers. At enrolment, mean age of 53 (range 17-95) and 49% were female. During a mean 3.1 years (range 0.01-6.5) of follow-up, 131/512 suspected VTE were adjudicated as recurrent VTE resulting in an annual risk of recurrent VTE of 6.7% (95% CI 5.5-7.6%) in patients with unprovoked VTE. Men had a 9.9% (95% CI 8.3-11.8%) annual risk of recurrent VTE. High risk women with 2 or more HERDOO points had an annual risk of recurrent VTE of 8.3% (95%CI 5.7-11.3%). Low risk women (1 or 0 HERDOO points) had 1.3% (95% CI 0.5-2.8%) annual risk of recurrent VTE compared to 9.5% (8.1-11.0%) annual risk of recurrent VTE in high risk patients (men and high risk women). Conclusions:Men and high risk women with unprovoked VTE should be considered for long-term OAC therapy given a high risk of recurrent VTE over 3 year follow-up . Women with a low HER DOO 2 score may be able to safely discontinue anticoagulants. Disclosures:Rodger:Bayer: Research Funding; Leo Pharma: Research Funding; Pfizer: Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Biomerieux: Research Funding; GTC Therapeutics: Research Funding. Crowther:BI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Leo Pharma: Consultancy, Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Artisan Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.