Idiopathic Venous Thromboembolism Research Articles

Frequencies of VKORC1-1639G>A and rs397509427 in Patients on Warfarin and Healthy Syrian Subjects.

Vitamin K epoxide reductase complex subunit 1 (VKORC1) gene encodes a key enzyme with multiple cellular activities, namely, the reduction of vitamin K to its active form. VKORC1-1639G>A (rs9923231) is a common single nucleotide polymorphism with a crucial impact on warfarin dosing and possibly other physiological functions. This study aimed at investigating the frequencies of VKORC1-1639G>A alleles and genotypes in Syrian healthy subjects and patients on warfarin for different indications. A total of 138 individuals were enrolled in this cross-sectional study. Genomic DNA was extracted from both patients on warfarin and healthy subjects, and polymerase chain reaction (PCR) specific amplicons were genotyped via standard sequencing which also allowed the detection of rs397509427. Comparisons of -1639G>A frequency with other populations were drawn. Of 94 patients on warfarin, 53 (56.38%) were with idiopathic venous thromboembolism (VTE). Despite comparable frequencies of the -1639A allele (47% and 50%), the AA and GA genotypes were at disparate frequencies of 93.2% versus 79.8% in the healthy subjects (n = 44) versus patients on warfarin, respectively. Carriers of the GG genotype were at a four-fold increased risk of VTE in comparison with those of the AA and GA genotypes (odds ratio (OR) = 4, 95% CI = 1.105 - 13.6, P = 0.0469). All study subjects were wild-type for the rs397509427 variant. Our results prove a high -1639A prevalence in Syrian healthy subjects and patients on warfarin at frequencies comparable to other Mediterranean and Middle Eastern populations. The A allele carriers are at a lower VTE risk, whereas a global prevalence gradient of the G allele is suggested to be associated with VTE risk.

Idiopathic Venous Thromboembolism and Metabolic Syndrome: A Meta-analysis.

Metabolic syndrome (MetS) is a recognised risk factor for arterial thromboembolism. However, whether MetS is also a risk factor for venous thromboembolism (VTE) is uncertain. PubMed, Embase, Web of science, and Cochrane databases were searched for case-control and cohort studies as well as conference proceedings of the International society on Thrombosis and Haemostasis (ISTH), and the Women's Health International Symposium Thrombosis and Hemostasis Branch (WHITH) published on or before March 1, 2021, to identify eligible studies. All included articles were assessed by two investigators using the Newcastle-Ottawa scale (NOS). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between VTE and MetS by using random or fixed-effects models. There were 31 case-control and 5 cohort studies with a total of 78,529 participants that fulfilled the inclusion criteria, MetS (OR 1.49; 95% CI 1.29-1.73) and its critical component obesity (OR 2.03; 95% CI 1.74-2.37), hypertension (OR 1.40; 95% CI 1.19-1.64) and diabetes mellitus (OR 1.22; 95% CI 1.01-1.48) were significant risk factors for VTE. MetS and its critical component obesity may contribute to the multifactorial pathogenesis of VTE. Key Words: Venous thromboembolism, Metabolic syndrome, Obesity.

Secondary prophylaxis of venous thromboembolism with direct oral anticoagulants: comparison between patients with major congenital thrombophilia versus non-thrombophilic patients.

Direct oral anticoagulants (DOACs) are widely used for the treatment and secondary prophylaxis of venous thromboembolism (VTE). Congenital thrombophilia is a condition that predisposes to a higher incidence of VTE and often requires long-term anticoagulation for secondary prophylaxis. It is less clear the efficacy of DOACs in patients with major thrombophilia. The aim of our study was to evaluate the efficacy and safety of full and reduced DOACs dose for VTE secondary prophylaxis, in patients affected by major congenital thrombophilia compared to a control group of patients with idiopathic recurrent VTE without thrombophilia. We retrospectively evaluated consecutive patients who required long-term anticoagulation for recurrent VTE, treated with DOACs, and compared the outcomes between patients affected by major thrombophilia and the control group. The examined patients were 209. The median time of DOACs therapy was 20months (range 6-90). Two (2.7%) thrombotic events were observed in the subset affected by major congenital thrombophilia (n = 72) and five (3.6%) in the control group (n = 137) (p 0.73). Four (5.5%) hemorrhagic events were reported in the group with major thrombophilia; 21 (15.3%) in the other group (p 0.039). No statistically significant differences were observed in terms of efficacy and safety between DOACs at full and reduced dose. Our data suggest that DOACs may be effective and safe in the secondary VTE prophylaxis in patients affected by major congenital thrombophilia, also at reduced dose.

Association between glycemic control and risk of venous thromboembolism in diabetic patients: a nested case\u2013control study

BackgroundPrevious studies suggested an elevated risk of venous thromboembolism (VTE) among patients with type 2 diabetes mellitus (T2DM), with a possible sex difference. The impact of glycemic control on the risk of VTE is unclear. Our objective was to analyze the association between glycemic control and the risk of unprovoked (idiopathic) VTE in men and women with T2DM.MethodsWe conducted a nested case–control analysis (1:4 matching) within a cohort of patients with incident T2DM between 1995 and 2019 using data from the CPRD GOLD. We excluded patients with known risk factors for VTE prior to onset of DM. Cases were T2DM patients with an unprovoked treated VTE. The exposure of interest was glycemic control measured as HbA1c levels. We conducted conditional logistic regression analyses adjusted for several confounders.ResultsWe identified 2′653 VTE cases and 10′612 controls (53.1% females). We found no association between the HbA1c level and the risk of VTE in our analyses. However, when the most recent HbA1c value was recorded within 90 days before the index date, women with HbA1c levels > 7.0% had a 36–55% increased relative risk of VTE when compared to women with HbA1c > 6.5–7.0%.ConclusionsOur study raises the possibility that female T2DM patients with HbA1c levels > 7% may have a slightly higher risk for unprovoked VTE compared to women with HbA1c levels > 6.5–7.0%. This increase may not be causal and may reflect differences in life style or other characteristics. We observed no effect of glycemic control on the risk of VTE in men.

Recommendations from the EGAPP Working Group: Routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members

Summary of RecommendationsThe Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found adequate evidence to recommend against routine testing for Factor V Leiden (FVL) and/or prothrombin 20210G>A (PT) in the following circumstances: (1) adults with idiopathic venous thromboembolism (VTE). In such cases, longer term secondary prophylaxis to avoid recurrence offers similar benefits to patients with and without one or more of these mutations. (2) Asymptomatic adult family members of patients with VTE and an FVL or PT mutation, for the purpose of considering primary prophylactic anticoagulation. Potential benefits are unlikely to exceed potential harms. The overall certainty of these findings was deemed “moderate.” The evidence was insufficient to determine whether FVL/PT testing might have clinical utility in some circumstances, such as for identifying FVL homozygosity among asymptomatic family members of adults with idiopathic VTE or counseling patients about the risks and benefits of antithrombotic therapy. Based on the available evidence, the certainty of net health benefit was deemed “low.” The recommendations do not extend to patients with other risk factors for thrombosis, such as contraceptive use, as the evidence review that serves as the basis for the recommendations focused primarily on idiopathic VTE. RationaleIn developing these recommendations the EGAPP Working Group considered evidence in the following three areas. Analytic ValidityThere is adequate evidence that testing accurately and reliably detects the R506Q (FVL) and 20210G>A (PT) variants in the Factor V and PT genes, respectively (a more complete definition of analytic validity, clinical validity, and clinical utility is contained under the “Clinical Considerations” section). Clinical ValidityThe presence of a heterozygous FVL variant seems to be a weak risk factor for recurrence of VTE (odds ratio [OR]: 1.56). Rare homozygous FVL mutations present somewhat greater risks of VTE recurrence (OR: 2.65). The evidence for this increased risk is convincing, but the magnitude of excess risk is not as great as previously thought. The evidence is insufficient to draw conclusions about excess VTE recurrence risk resulting from compound heterozygosity (FVL and PT), but it is likely to be at least as high as with FVL alone. The OR for compound heterozygosity is 6.69. The evidence is insufficient to draw conclusions about VTE recurrence risks associated with PT mutations alone. For family members of index VTE cases, there is convincing evidence that both heterozygosity and homozygosity for FVL are associated with higher risks for VTE occurrence (ORs 3.49 and 17.84, respectively) than for family members without FVL variants. Clinical UtilityThere is convincing evidence that longer term secondary prophylaxis after an initial idiopathic VTE event yields comparable benefits to those with and without a FVL or PT mutation. For asymptomatic family members of index cases, no prophylaxis trials have been reported. Hence, there is no direct evidence of particular benefit to family members. Potential net harm is possible if primary prophylaxis is administered to asymptomatic family members with one or more mutations, because the absolute risk of an initial VTE event is low, and the risk of anticoagulant-induced hemorrhage is relatively high.

The Risk of Venous Thromboembolism (VTE) in Men with Benign Prostatic Hyperplasia Treated with 5-Alpha Reductase Inhibitors (5ARIs).

BackgroundMany men receive 5-alpha reductase inhibitors (5ARIs) for ongoing treatment of benign prostatic hyperplasia (BPH). The increased risk of cardiovascular complications with 5ARIs has been documented in BPH studies and the occurrence of cerebral venous thrombosis, presumably due to increased estrogen level following 5ARI use, was described in multiple case reports. The objective of this study was to determine if 5ARIs with or without alpha blockers (AB) were associated with an increased risk of venous thromboembolism (VTE) in males with BPH.MethodsWe conducted a nested case–control study among a population of men ages 40–79 who received at least one 5ARI or AB prescription for treatment of BPH between 1995 and 2015 in the UK-based Clinical Practice Research Datalink GOLD. Cases of incident VTE (pulmonary embolism [PE] or deep venous thrombosis [DVT]) and matched controls were identified from this population. We used descriptive analyses and conditional logistic regression to evaluate the risk of VTE in users of 5ARIs compared to users of ABs.ResultsFor 5ARI only users, the adjusted odds ratios (aORs), (95% CI) for VTE were 1.51 (0.98–2.32) in current 5ARI users and 1.23 (0.70–2.17) in recent/distant past, compared to AB only users. However, the aOR (95% CI) in men who had 50 or more current 5ARI prescriptions compared to users of ABs only was higher: 2.29 (1.14–4.63). For 5ARI with AB use, the aORs, (95% CI) for VTE were 1.16 (0.64–2.10) in current 5ARI+AB users and 1.93 (0.71–5.25) in recent/distant past, compared to AB only users. The aOR (95% CI) in men who had 50 or more current 5ARI+AB prescriptions compared to users of ABs only was 1.65 (0.64–4.26).ConclusionCurrent use of 5ARI, particularly long-term use, is associated with an increased risk of incident idiopathic VTE compared to patients treated with AB use only.

Factors affecting the recurrence in patients with venous thromboembolism: A retrospective cohort study.

Background The aim of the study was to evaluate the frequency of recurrence and the risk factors for recurrence in patients who were diagnosed with venous thromboembolism. Methods Between January 2005 and January 2015, a total of 412 venous thromboembolism patients (164 males, 248 females; mean age: 53.5±16.6 years; range: 19 to 95 years) were retrospectively analyzed. The demographics, underlying risk factors, comorbidities, imaging findings, and treatment data of the patients were recorded. Results At least one transient/permanent risk factor was found in 341 (82.7%) of the index events, and the other 71 (17.2%) were idiopathic. Recurrence developed in 76 (18.4%) of the patients. The duration of the treatment in the first event was significantly longer in recurrent cases (p=0.007). The recurrence rate in patients diagnosed with only deep vein thrombosis or patients diagnosed with pulmonary thromboembolism + deep vein thrombosis was significantly higher than the patients diagnosed with only pulmonary thromboembolism (24% vs. 14.2%, respectively; p=0.007). The rate of idiopathic venous thromboembolism was higher in recurrent cases than in non-recurrent cases (26.3% vs. 15.2%, respectively; p=0.028). At the end of the first year, the mean D-dimer levels were higher in recurrent cases (p=0.034). Hereditary risk factors were also higher in recurrent cases (39.5% vs. 19.3%, respectively; p=0.031). There was no significant correlation between recurrence and mortality. Conclusion The presence of deep vein thrombosis, idiopathic events, high D-dimer levels at the end of the first year and hereditary risk factors seem to be associated with recurrence.

An Ex Vivo Analysis of Thrombin Generation and Thromboelastometry in Patients Undergoing Treatment with Rivaroxaban Demonstrates Sustained Anticoagulant Effect and High Inter-Individual Variability

Background : Rivaroxaban, 20 mg orally administered once daily, is widely used for secondary prevention of venous thromboembolism (VTE) without the need for routine laboratory monitoring. It is licensed for the prevention of VTE after major orthopedic surgery, for the treatment of acute symptomatic VTE, the secondary prevention of VTE and for prevention of stroke in patients with non-valvular atrial fibrillation. Rivaroxaban selectively and competitively inhibits free factor Xa (FXa) and prothrombinase/clot-associated FXa through reversible interactions thereby inhibiting thrombin generation and decreasing fibrin clot formation. The need of laboratory evaluation of rivaroxaban is actually questioned.Aim : In patients treated for secondary prevention of VTE, we evaluated ex vivo the anticoagulant potency of rivaroxaban treatment at different times after drug intake.Methods : 97 patients (39 males, 58 females; median age: 59 years) with idiopathic VTE were treated with rivaroxaban (20 mg/day) for a period longer than 6 months and compared to 30 controls age and sex-matched. Rivaroxaban concentrations (STA®-Liquid Anti-Xa), thrombin generation (PPP-reagent 5 pM TF; calibrated automated thrombogram, Stago France) and whole blood thromboelastometry (5 pM tissue factor; ROTEM® Werfen) were assessed. The interval between drug intake and blood sampling was registered.Results : Treatment with rivaroxaban significantly inhibited thrombin generation (TG) and prolonged clotting time (CT): 93% of patients had TG inferior to the lower normal limit and 77% had CT longer than the upper normal limit. This effect in both assays, was not correlated to its plasma concentrations, it was significant from the 1st hour after drug intake and persisted at similar levels during the daily therapeutic cycle even at low concentrations (30 ng/ml). Rivaroxaban had no effect on clot firmness. The inter-individual coefficient of variation of rivaroxaban concentrations and TG/ROTEM alterations after drug intake ranged from 50% to 100%.Conclusion : Once daily administration of rivaroxaban induces sustained daily anticoagulant effect, detected by TG and ROTEM assays, with no significant changes related to drug concentration reduction. This profile could explain the wide therapeutic window and the favorable benefit risk ratio of the treatment with rivaroxaban. Due to the high variability the identification of patients with extreme values of TG could be useful strategy for treatment optimization on individual basis. DisclosuresNo relevant conflicts of interest to declare.

Coagulation Activation in Brain Neoplasms

Introduction:Cancer patients are at increased risk for venous thromboembolism (VTE), and patients with brain tumors have a VTE risk of up to 30% over the course of the disease. Factors contributing to VTE risk include age ≥60 years, obesity, glioblastoma histology, large tumor size, subtotal resection, leg paresis and treatment with surgery, radiation or chemotherapy.Coagulation activation occurs in cancer patients via several mechanisms including up-regulation of tumor or microparticle-associated tissue factor (TF) and procoagulant molecules, downregulation of tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), increased plasminogen activator inhibitor (PAI-1), all resulting in increased thrombin generation and a systemic prothrombotic state.We hypothesized that patients with glioblastoma multiforme (GBM), a high-grade malignant brain tumor, exhibit increased systemic coagulation activation compared to healthy individuals and patients with benign meningiomas. We tested this hypothesis by measuring thrombin generation (TG) as a surrogate marker of systemic coagulation activation in patients with GBM and meningiomas and in age and sex matched healthy controls for comparison.Methods:This study was supported by grants from the Northern New England Clinical Oncology Society and the Neuro-oncology section at Dartmouth-Hitchcock Medical Center. The primary objective was to compare the pre-surgical peak TG in the GBM and healthy control groups. Secondary objectives were to 1) compare pre-surgical peak TG in the meningioma and healthy control groups and 2) compare tumor volumes on MRI with TG in patients with GBM and meningiomas.Patients with a new GBM or meningioma (W.H.O. grade 1 or 2) for whom a debulking procedure or surgical resection was planned were eligible. Patients with an additional active malignancy, history of idiopathic VTE at any time or provoked VTE within 5 years of entry, current treatment with an anticoagulant for any reason within the last 90 days or a surgical procedure other than a skin biopsy within the previous 30 days were excluded.After informed consent, 20 mL of blood was collected from subjects in 3.2% sodium citrate tubes prior to surgery. An additional 20 ml of blood was collected from GBM subjects 3 to 6 weeks after surgery. Platelet-poor plasma was prepared by centrifugation and stored at -80°C until analysis. TG was measured in nanomoles (nm) with a calibrated automated thrombogram assay (Thrombinoscope BV, Maastricht, Netherlands) using 1 pM TF and 4 uM phospholipids to trigger coagulation reactions. Statistical analysis was performed using Student's t-test for comparisons between groups.All GBM and meningioma subjects had pre-operative MRI scans. The highest resolution available gadolinium-enhanced anatomic scan (MPRAGE, T1-FLAIR, BRAVO, etc) was manually segmented by one of two trained segmenters to label tumor areas, with results reviewed, adjusted, and confirmed by a practicing neuroradiologist. Tumor volumes were then calculated as the number of labeled voxels times voxel volume (0.39-4.64 mm^3).Results:Fifty-eight patients consented to participate in the study. There were 15 screen failures and of the 43 patients included in the study, 20 had GBM and 23 had meningiomas. Blood from one age and sex-matched healthy blood donor was obtained for each study subject. The mean peak pre-op TG was 290 +/- 53 nm in the GBM cohort and 186 +/- 41 nm in controls; 242 +/- 55 nm in the meningioma cohort and 177 +/- 57 in controls. The p-value was <0.001 for all three pairwise comparisons. Only 9 post-op GBM samples were available for analysis. In this group, the mean pre-op TG was 323 nm +/- 38 nM and 273 nm +/- 47 nM post-op (p < 0.001). Two patients in the GBM group developed VTE with a mean peak TG of 364 nm compared to 290 nm for GBM patients without VTE (P = 0.04). We found no association between tumor volumes and pre-op TG.Conclusions:Peak TG was significantly higher in patients with GBM than in either patients with meningioma or healthy controls. TG decreased after tumor debulking surgery in GBM patients. Moreover, our results suggest that TG may be a useful marker for systemic coagulation activation in patients with GBM. Though our early results showing increased TG in GBM patients with VTE are provocative, more study is required to determine whether TG can be used to reliably predict VTE risk in this population. DisclosuresNo relevant conflicts of interest to declare.

Risk scores for occult cancer in patients with unprovoked venous thromboembolism: Results from an individual patient data meta‐analysis

BackgroundThe Registro Informatizado de Pacientes con Enfermedad TromboEmbólica (RIETE) score and the Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) risk scores aim to identify patients with acute unprovoked venous thromboembolism (VTE) at high risk of occult cancer, but their predictive performance is unclear. MethodsThe scores were evaluated in an individual patient data meta‐analysis. Studies were eligible if enrolling consecutive adults with unprovoked VTE who underwent protocol‐mandated screening for cancer. The primary outcome was a cancer diagnosis between 30 days and 2 years of follow‐up. The discriminatory performance was evaluated by computing the area under the receiver (ROC) curve in random‐effects meta‐analyses. ResultsThe RIETE score could be calculated in 1753 patients, of whom 63 (3.6%) were diagnosed with cancer. The pooled area under the ROC curve was 0.59 (95% confidence interval [CI], 0.52‐0.66; I2 = 0%). Of the 427 patients (24%) classified as high risk, 25 (5.9%) were diagnosed with cancer compared with 38 of 1326 (2.9%) low‐risk patients (hazard ratio [HR], 2.0; 95% CI, 1.3‐3.4). The SOME score was calculated in 925 patients, of whom 37 (4.0%) were diagnosed with cancer. The pooled area under the ROC curve was 0.56 (95% CI, 0.46‐0.65; I2 = 46%). Of the 161 patients (17%) classified as high risk (≥2 points), eight (5.0%) were diagnosed with cancer compared with 29 of 764 (3.8%) low‐risk patients (HR, 1.2; 95% CI, 0.55‐2.7). ConclusionsThe predictive discriminatory performance of both scores is poor. When used dichotomously, the RIETE score is able to discriminate between low‐ and high‐risk patients. Because this is largely driven by advanced age, these results do not support the use of these scores in daily clinical practice.

Cerebral paradoxical embolism associated with patent foramen ovale and idiopathic venous thromboembolism in a 31-year-old patient.

ABSTRACTParadoxical embolism is the passage of venous thrombi into the arterial circulation through a pulmonary or intracardiac shunt. We report the management of a 31-year-old patient who initially presented with chest pain and right brachiofacial paresis. A diagnosis of paradoxical cerebral embolism associated with a spontaneous venous thromboembolism and a patent foramen ovale was made. The patient benefited from thrombolytic therapy and lifelong anticoagulation with good recovery. This case showed that percutaneous closure of a patent foramen ovale needs to be discussed individually.

Identification of a Whole Blood Signature for Venous Thromboembolism

Venous thromboembolism (VTE), comprised of deep vein thrombosis and pulmonary embolism, is a common health problem both in the United States and worldwide, with significant associated morbidity and mortality. Despite multiple known genetic and situational risk factors, an estimated 30% of all events remain classified as idiopathic, demonstrating a significant knowledge gap in the pathophysiology VTE. While platelets are well established as an essential contributor to thrombus formation and there has been recent interest in the role of neutrophil extracellular traps, specific cell types and pathways involved in the pathogenesis of VTE remain uncertain. In this study, our primary aims were to define a unique transcriptional signature for VTE and to identify the types of cells and specific pathways involved in development of VTE.Whole blood was collected in PAX gene tubes and RNA sequencing for coding mRNA was performed in an unbiased manner in 201 patients with prevalent VTE as well as 43 healthy controls. We used a bioinformatics approach to develop a unique signature for VTE by identifying differentially expressed genes, developing cell-type modules, and ascertaining pathways driving differentially expressed transcripts. We performed additional analyses on subgroups of patients with idiopathic VTE, patients with incident VTE, and VTE patients matched to healthy controls by age and sex. We went on to use machine learning methods to learn models that best differentiate VTE patients from healthy controls and validated it on a left out test set within our VTE population.Genes specific to neutrophils, erythrocytes, and platelets, in that order, were most significantly upregulated in patients with VTE compared to healthy controls. Genes related to T-cells were downregulated. Pathway analysis revealed upregulated neutrophil activation and degranulation, erythrocyte differentiation and homeostasis, and platelet degranulation. A gene signature of 217 transcripts was outstanding at differentiating patients with VTE versus healthy controls (AUC 0.94). Following adjustment for age, sex, and race/ethnicity our genetic signature remained significantly robust at differentiating patients with VTE versus controls (AUC 0.83). Our expression signature remained stable across patients with idiopathic VTE (AUC 0.93), and in patients who went on to develop future VTE events (AUC 0.95).In summary, we have demonstrated a whole blood transcriptional signature for prevalent and incident VTE. Genes related to neutrophils, erythrocytes, and platelets are upregulated in patients with VTE and genes related to T-cells were downregulated. These findings suggest an active role of cell types once thought to be passively entrapped within thrombus and provide new areas of study to establish the pathophysiology of VTE. DisclosuresNo relevant conflicts of interest to declare.

Extended Treatment with Apixaban for Venous Thromboembolism Prevention in the Netherlands: Clinical and Economic Effects.

Background Dutch guidelines advise extended anticoagulant treatment with direct oral anticoagulants or vitamin K antagonists for patients with idiopathic venous thromboembolism (VTE) who do not have high bleeding risk. Objectives The aim of this study was to analyze the economic effects of extended treatment of apixaban in the Netherlands, based on an updated and adapted previously published model. Methods We performed a cost-effectiveness analysis simulating a population of 1,000 VTE patients. The base-case analysis compared extended apixaban treatment to no treatment after the first 6 months. Five additional scenarios were conducted to evaluate the effect of different bleeding risks and health care payers' perspective. The primary outcome of the model is the incremental cost-effectiveness ratio (ICER) in costs (€) per quality-adjusted life-year (QALY), with one QALY defined as 1 year in perfect health. To account for any influence of the uncertainties in the model, probabilistic and univariate sensitivity analyses were conducted. The treatment was considered cost-effective with an ICER less than €20,000/QALY, which is the most commonly used willingness-to-pay (WTP) threshold for preventive drugs in the Netherlands. Results The model showed a reduction in recurrent VTE and no increase in major bleeding events for extended treatment in all scenarios. The base-case analysis showed an ICER of €9,653/QALY. The probability of being cost-effective for apixaban in the base-case was 70.0% and 91.4% at a WTP threshold of €20,000/QALY and €50,000/QALY, respectively. Conclusion Extended treatment with apixaban is cost-effective for the prevention of recurrent VTE in Dutch patients.

Risk Scores for Occult Cancer in Patients with Venous Thromboembolism: A Post Hoc Analysis of the Hokusai-VTE Study.

Venous thromboembolism (VTE) may be the first sign of an undiagnosed cancer. In patients with unprovoked VTE, the risk is approximately 5% in the year following VTE diagnosis. Cancer-specific screening is therefore often considered in these patients, but the optimal screening strategy remains controversial. Recently, two risk classification scores have been proposed that may help in identifying patients at high risk of occult cancer in whom extensive screening may be warranted. In the present post hoc analysis of the Hokusai-VTE study, we evaluated the performance of the Registro Informatizado de Pacientes con Enfermedad TromboEmbólica (RIETE) and Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) scores for occult cancer in patients with acute VTE. A total of 8,032 patients were included in the analysis of whom 218 (2.7%; 95% confidence interval [CI], 2.4-3.1) developed cancer between 30-day and 12-month follow-up. The c-statistics of the RIETE and SOME scores were 0.62 (95% CI, 0.57-0.66) and 0.59 (95% CI, 0.55-0.62), respectively. In patients classified as 'high risk', the cumulative incidence of cancer diagnosis during follow-up was 2.9% (95% CI, 2.1-3.9) for the RIETE score and 2.7% (95% CI, 1.9-3.7) for the SOME score, corresponding to hazard ratios of 1.8 (95% CI, 1.3-2.5) and 1.5 (95% CI, 1.04-2.2), respectively. In conclusion, the performance of both scores was poor. When used dichotomously, the scores were able to identify a group of patients with a significantly higher risk of occult cancer, although it remains unknown whether this translates into improved clinical important outcomes.

Idiopathic Venous Thromboembolism (VTE) and its Association to Rare Molecular Clotting Abnormalities

Idiopathic Venous Thromboembolism (VTE) and its Association to Rare Molecular Clotting Abnormalities

Bidirectional risk between venous thromboembolism and cancer in East Asian patients: synthesis of evidence from recent population-based epidemiological studies.

BackgroundUnprovoked (idiopathic) venous thromboembolism (VTE) with no obvious antecedent risk factors, is associated with a significant risk of subsequent occult cancer. Conversely, there is a heightened risk of VTE in cancer patients. This bidirectional risk can be estimated from population-based cohort studies conducted in East Asians.MethodsA literature search using medical subject heading terms and Boolean logic in PubMed and MedLine was performed in April 2017. Twenty-two papers reported from East Asia were retrieved for study and data synthesis. Proportional meta-analysis with a random-effects model was used to synthesize data with 95% confidence intervals (CIs) when appropriate.ResultsSynthesis of data on VTE incidence in the East Asian population (I2 = 76.2%) showed that pooled incidence was 20.3 (95% CI, 11.2–32) per 100,000 person-years. VTE incidence steadily increased with age. Unprovoked VTE accounted for 35% (95% CI, 24%–48%) of all cases of incident VTE (I2 = 99.7%). The overall cancer risk was significantly higher (2.3-fold) in the VTE cohort than in comparators. Among the patients with unprovoked VTE, approximately 7% had a subsequent cancer diagnosis within 2 years of the first episode of idiopathic VTE. The risk of VTE recurrence was increased in cancer patients (adjusted odds ratio, 1.64; 95% CI, 1.26–1.99). VTE incidence was 9.9 per 1,000 person-years in cancer patients, particularly in liver, pancreas, and lung cancer patients.ConclusionNewly diagnosed VTE incidence is estimated at approximately 4,400 new cases annually in Taiwan and 7,100 in South Korea. Similar to the trend in VTE incidence among the general population, VTE risk in East Asian cancer patients is markedly lessened.

Effect of testing for cancer on cancer- and venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE.

Venous thromboembolism (VTE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonary embolism (PE). A proportion of patients with VTE have no underlying or immediately predisposing risk factors and the VTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlying malignancy. This has raised the question of whether patients with an unprovoked VTE should be investigated for an underlying cancer. Treatment for VTE is different in cancer and non-cancer patients and a correct diagnosis would ensure that patients received the optimal treatment for VTE to prevent recurrence and further morbidity. Furthermore, an appropriate cancer diagnosis at an earlier, potentially curative stage could avoid the risk of cancer progression and thus lead to improvements in cancer-related mortality and morbidity.To determine whether testing for undiagnosed cancer in patients with a first episode of unprovoked VTE (DVT or PE) is effective in reducing cancer and VTE-related mortality and morbidity and to establish which tests for cancer are most useful.The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (CRS) (2014, Issue 12). Clinical trials databases were searched. The reference lists of relevant articles were also checked.Randomised and quasi-randomised trials in which patients with an unprovoked VTE were allocated to receive specific tests for cancer or clinically indicated tests only were eligible for inclusion in this review. Primary outcomes included all-cause mortality, cancer-related mortality and VTE-related mortality.Selection of the studies, quality assessment and data extraction were completed independently by two review authors. Any disagreements were resolved by discussion.Two studies with a combined total of 396 patients met the inclusion criteria for this review. Both studies assessed the effect of testing for cancer versus clinically indicated tests only in patients with an unprovoked VTE. The quality of the evidence was moderate because although the studies were judged to be at low or unclear risk of bias, there was concern that the studies were small as reflected in the wide confidence intervals (CIs). Pooled analysis showed that testing for cancer was consistent with either a benefit or no benefit on cancer-related mortality (odds ratio (OR) 0.49, 95% CI 0.15 to 1.67, P = 0.26). One study showed that, overall, malignancies were less advanced in patients belonging to the extensive screening group than in patients of the control group (64% versus 20%, P = 0.047) and that tested patients were diagnosed earlier than untested patients (mean 1 month versus 11.6 months to cancer diagnosis from the time of diagnosis of VTE). Standard deviations were not provided for time to diagnosis, so it was not possible to perform an independent statistical analysis on this association. Neither study measured all-cause mortality, VTE-related morbidity and mortality, side effects of anticoagulation, side effects of cancer tests or patient satisfaction.Testing for cancer in patients with idiopathic VTE leads to earlier diagnosis of cancer at an earlier stage of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the effectiveness of testing for undiagnosed cancer in patients with a first episode of unprovoked VTE (DVT or PE) in reducing cancer and VTE-related morbidity and mortality. The results are imprecise and could be consistent with either harm or benefit. Further good-quality large-scale randomised controlled trials are required before firm conclusions can be made.

Early diagnosis of venous thromboembolism as a clinical primary symptom of occult cancer: Core proteins of a venous thrombus.

Malignancy is one of the risk factors of venous thromboembolism (VTE). As a common accompanying factor of malignant tumors, almost 20% of idiopathic VTEs are identified in patients with occult types of cancer as the primary symptom. The type of internal association that exists between malignant tumors and VTE has not yet been determined. The present review discusses the following: i) Reversible combinations between core proteins of venous thrombi and their ligand proteins. With the condition of immune cell balancing function collapse, which is characterized as dysfunction immune cells and impaired immune functions, the human body loses the function of eliminating infectious/malignant cells quickly and effectively. Thus, integrins β2 and β3 on the membrane of platelets and white blood cells are activated to combine with fibrinogen ligands to form an intravenous mesh-like structure, which acts as an intravenous biological filter that prevents infectious/malignant cells from flowing back into the circulatory system. During the defense process, blood cells (mainly red blood cells) stagnate and fill the filter, which results in venous thrombotic diseases. ii) Tumor cells, which cannot be eliminated quickly, proliferate and invade; or ischemic necrosis destroys peripheral tissues and vessels (veins and arteries), resulting in the formation of a biological filter in injured veins. The filter is filled with stranded tumor cells, which prevents the hemorrhagic metastasis of malignant cells. The formation of an intravenous biological filter results from the transition of the body's own defense capabilities, which is also a physical/histopathological phenomenon. iii) An increase in the number of core proteins in a venous thrombus is a basic molecular step in the formation of intravenous biological filters, which is also defined as a marker of the newly initiated defensive barrier. Increased levels of integrins β1, β2 and β3 are useful in not only the specific diagnosis of VTE, but also in the early recognition of occult malignant tumors in idiopathic VTE patients.

Screening for occult cancer in idiopathic venous thromboembolism — Systemic review and meta-analysis

BackgroundIdiopathic venous thromboembolism (VTE) may be associated with an occult malignancy. Early detection of cancer might be translated to a better prognosis for these patients. However, the efficacy of extensive screening for cancer in patients with idiopathic VTE is controversial. Materials and methodsSystemic review and meta-analysis of all available prospective trials comparing extensive to limited screening for occult malignancies in patients with idiopathic VTE.Primary outcome: all-cause mortality. Secondary outcomes: cancer related mortality, early cancer diagnosis, cancer diagnosis at the end of follow up and cancer diagnosis at an early stage. Risk ratios (RR) with 95% confidence intervals (CIs) were estimated and pooled. ResultsThe study included five trials and 2287 patients. Extensive screening did not affect all-cause mortality at the end of follow up [RR 0.86 (95% CI 0.58–1.27)] or cancer-related mortality [RR 0.93 (95% CI 0.54–1.58)]. Yet, it yielded more diagnoses of cancer [RR 2.17 (95% CI 1.42–3.32)]. Rates of cancer diagnosis at an early stage did not differ statistically between the two groups [RR 1.49 (95% CI 0.86–2.56)]. However, analysis of the randomized controlled trials alone showed a tendency towards early stage cancer at diagnosis in extensive screening group in, with results almost statistically significant [RR 2.14 (95% CI 0.98–4.67), p=0.06]. ConclusionsExtensive screening for malignancy after idiopathic VTE does not affect mortality rates. Yet, it yields more cancer diagnoses shortly after the VTE event. Further research is needed to determine whether extensive screening might be proper for specific high risk populations.

Idiopathic inflammatory myopathy and the risk of venous thromboembolism: a meta-analysis.

This study aimed at analyzing published data on the association between idiopathic inflammatory myopathy and venous thromboembolism (VTE). We examined studies on VTE risk in patients with polymyositis (PM) and/or dermatomyositis (DM), in the MEDLINE, EMBASE, and Cochrane databases and via manual searches. We performed a meta-analysis on the relative risks (RRs) of VTE, pulmonary embolism (PE), and deep vein thrombosis (DVT) in these patients. Five studies, including 8858 patients with PM/DM met the inclusion criteria. Meta-analysis revealed a significant association between PM/DM and VTE risk (RR=4.364, 95% CI 2.128-8.949, p=5.8×10-5). A significant association was found between PE risk and PM/DM (RR=3.504, 95% CI 2.856-4.300, p<1.0×10-8). Meta-analysis also indicated a significant association between DVT risk and PM/DM (RR=7.481, 95% CI 3.355-16.68, p=8.7×10-7). This meta-analysis demonstrated that both types of PM/DM are associated with an elevated risk of VTE, PE, and DVT, suggesting that patients with PM/DM should be carefully monitored for development of these conditions.