Toll-like receptor 9 gene expression in the post-thrombotic syndrome, residual thrombosis and recurrent deep venous thrombosis: A case-control study

Animal models suggest that toll-like receptor 9 (TLR9) promotes thrombus resolution after acute deep venous thrombosis (DVT). We hypothesized that TLR9 expression is lower in patients with post-thrombotic syndrome (PTS) and investigated the role of TLR9 in residual thrombosis (RT) and recurrence. Patients with a history of DVT with PTS (cases, n=30) and without PTS after minimal 24 months follow-up (controls, n=30) were selected. Healthy individuals (HI, n=29) without DVT were included as reference. TLR9 mRNA expression in leukocytes was determined by qPCR and normalized to the housekeeping succinate dehydrogenase subunit A gene using the ΔCt method. Sub analyses were performed to explore the TLR9 expression in patients with and without RT and multiple DVT episodes. The median TLR9 expression was 0.45 (interquartile range 0.31 to 0.93), 0.39 (0.25 to 0.69) and 0.62 (0.32 to 0.75) in cases, controls and HI respectively (p=0.61). The median TLR9 expression was 0.39 (0.26 to 0.51) in patients with RT compared to 0.55 (0.30 to 0.86, p=0.13) in those without. The median TLR9 expression was significantly lower in patients who had one DVT compared to patients with recurrent DVT, 0.37 (0.23 to 0.63) versus 0.55 (0.43 to 0.96) respectively (p <0.01). No significant difference in TLR9 expression was found between cases, controls and HI. However TLR9 expression seems lower in individuals with DVT and RT, albeit not significant. Interestingly, TLR9 might play a role in recurrent DVT, as the TLR9 expression was significantly higher in patients with recurrent DV

Individualised versus standard duration of elastic compression therapy for prevention of post-thrombotic syndrome (IDEAL DVT): a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial

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Platelet Dysfunction in Thrombosis Patients Treated with Vitamin K Antagonists and Recurrent Bleeding

BACKGROUND: Recurrent bleeding can complicate the treatment of thrombosis patients with vitamin K antagonists (VKA), even at a well-regulated level of anticoagulation. In this proof-of-principle study, we investigated whether alterations in platelet function or von Willebrand factor (vWf) contribute to a bleeding phenotype in these patients. METHODS: In this case-control study 33 well-regulated patients without bleeding events (controls) and 33 patients with recurrent bleeding (cases) were retrospectively included. Thrombin generation and vWf were determined in plasma. Platelet function was assessed by light transmission aggregometry and flow cytometry using a validated panel of agonists. RESULTS: Thrombin generation was similarly reduced in controls and cases, in comparison to normal plasma. Plasma vWf level was above the normal range in 85% of controls and 67% of the cases. vWf activity was similarly increased in all patients in comparison to healthy volunteers. Platelet aggregation was in the normal range for almost all patients irrespective of the type of agonist. However, in response to a low collagen dose, platelets from 21% of controls and 27% of cases showed diminished responses. Agonist-induced secretion of alpha- and dense-granules or integrin αIIbβ3 activation were affected in platelets from neither controls nor cases. CONCLUSION: Recurrent bleeding in well-controlled patients on VKA therapy is not explained by anti-hemostatic changes in platelet or vWf function

Individually shortened duration versus standard duration of elastic compression therapy for prevention of post-thrombotic syndrome:a cost-effectiveness analysis

Background: The IDEAL DVT study showed that it was safe to shorten the duration of elastic compression therapy on an individualised basis after deep vein thrombosis for prevention of post-thrombotic syndrome. In this study, we assessed the cost-effectiveness of this strategy. Methods: IDEAL DVT was a multicentre, randomised, non-inferiority trial that included patients with acute proximal deep vein thrombosis of the leg. After 6 months of elastic compression therapy, patients were randomly assigned (1:1) to the standard 2 years of elastic stocking compression therapy or shortened duration of compression therapy based on the patient's Villalta score. For our cost-effectiveness analysis, we assessed quality-adjusted life-years (QALYs), measured with the three-level version of EQ-5D (EQ-5D-3L; Dutch and UK tariff) and the 36-item Short Form Health Survey (SF-36), and costs in € (health-care and societal perspective) according to the intention-to-treat approach. Data were collected at 3, 6, 12, and 24 months after diagnosis of thrombosis. We calculated incremental net monetary benefit using a QALY threshold of €30 000, and obtained bootstrapped means and 95% CIs. IDEAL DVT is registered with ClinicalTrials.gov, number NCT01429714. Findings: Between March 22, 2011, and July 1, 2015, 865 patients were enrolled in IDEAL DVT. 437 were assigned to individualised duration of elastic compression therapy and 428 to standard duration of elastic compression therapy. Nine patients were eventually excluded because of recurrent venous thromboembolism within 6 months after the first event. From a societal perspective, for every QALY lost measured with the EQ-5D Dutch tariff, cost savings were €305·992 (incremental net monetary benefit €3205, 95% CI 502–5741), and for every QALY lost based on the Short-Form Six-Dimension (SF-6D) utility score (derived from SF-36), cost savings were €6030·941 (€3540, 95% CI 1174–5953). Using the UK tariff for EQ-5D, the individualised strategy was more effective and less costly (€4071, 1452–6647). The probability that the individualised strategy was cost-effective was 99% at a threshold of €30 000 per QALY (EQ-5D Dutch tariff). Interpretation: Individually shortened duration of elastic compression therapy was cost-effective compared with standard duration elastic compression therapy. Use of an individualised approach to elastic stocking compression therapy for the prevention of post-thrombotic syndrome after deep vein thrombosis could lead to substantial costs savings without loss in health-related quality of life. Funding: Netherlands Organisation for Health Research and Development

Individualised versus standard duration of elastic compression therapy for prevention of post-thrombotic syndrome (IDEAL DVT):A multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial

Therapy with elastic compression stockings has been the cornerstone for prevention of post-thrombotic syndrome for decades in patients after acute deep venous thrombosis. It is uncertain who benefits most from therapy, and what the optimum duration of therapy should be. We therefore aimed to assess the safety and efficacy of individualised duration of compression therapy versus the standard duration of 24 months following an initial treatment period of 6 months. We did a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial at 12 hospitals in the Netherlands and two in Italy. We randomly assigned patients (1:1) with acute proximal deep vein thrombosis of the leg and without pre-existent venous insufficiency (Clinical Etiological Anatomical and Pathophysiological score <C3) to receive either individualised duration of elastic compression therapy or standard duration of therapy for 24 months following an initial treatment period of 6 months. Randomisation was done with a web-based automatic randomisation programme (TENALEA) and a random block size (2-12), and was stratified by centre, age, and body-mass index. In the initial phase, compression was applied within 24 h of diagnosis according to three prespecified protocols. All patients received elastic compression stockings (30-40 mm Hg) for 6 months, and were instructed to wear them every day during ambulant hours. Thereafter treatment was tailored on the basis of clinical signs and symptoms scored according to the Villalta post-thrombotic syndrome scale; patients assigned to individualised therapy with two consecutive Villalta scores of 4 or less were instructed to stop using the stockings. Patients were followed up for 2 years and assessed at five clinic visits at study inclusion, and 3, 6, 12, and 24 months after diagnosis (stocking allocation was not revealed to the assessors). The primary outcome was the proportion of patients with post-thrombotic syndrome at 24 months diagnosed according to original Villalta criteria (a score of ≥5 on two consecutive occasions at least 3 months apart) assessed by intention to treat. The predefined non-inferiority margin for the difference in success rates was set at 7·5%. This study has been completed and is registered with ClinicalTrials.gov, number NCT01429714. Between March 22, 2011, and July 1, 2015, we enrolled 865 patients and randomly assigned 437 to individualised duration compression stockings and 428 to standard duration. 283 (66%) of 432 patients in the intervention group were advised before 24 months to stop wearing elastic compression stockings (236 [55%] of 432 patients after 6 months, and 47 [11%] of 432 at 12 months). Post-thrombotic syndrome occurred in 125 (29%) of 432 patients receiving individualised duration of therapy and in 118 (28%) of 424 receiving standard duration of therapy (odds ratio for difference 1·06, 95% CI 0·78 to 1·44). The absolute difference was 1·1% (95% CI -5·2 to 7·3), thus meeting the non-inferiority margin. 24 patients died, 17 (4%) in the individualised treatment group and seven (2%) in the standard duration group, but no deaths were related to treatment. No serious adverse events related to the intervention occurred. Individualised therapy with elastic compression stockings for the prevention of post-thrombotic syndrome was non-inferior to standard duration of therapy of 24 months. Individualising the duration is effective and could shorten the length of therapy needed, potentially enhancing patients' wellbeing. ZonMw (Netherlands