Molecular determinants of thrombosis recurrence risk across venous thromboembolism subtypes.

Venous thromboembolism (VT) is a frequent (annual incidence of 1 to 2 per 1,000) and potentially life-threatening (case-fatality rate up to 10%) disease. VT is associated with serious short-term and long-term complications including a recurrence rate of approximately 20% within five years. Anticoagulant therapy, the mainstay of VT treatment, drastically reduces the risk of early VT recurrence, but it exposes patients to a substantial risk of bleeding. We analysed the genomic architecture of VT recurrence using data from 6,571 patients across eight cohorts, 1,816 of whom experienced recurrence, with a particular focus on the clinical manifestation of the type of first VT event. Through genome-wide association studies (GWAS), we identified three loci significantly associated (P<5×10-8) with VT recurrence in the general VT population: GPR149/MME, L3MBTL4, and THSD7B. Protein Quantitative Trait Locus and Mendelian Randomization analyses further identified elevated plasma levels of coagulation factor XI and GOLM2 as risk factors for recurrence, while decreased levels of PCSK9 and pro-IL16 were linked to reduced VT recurrence risk. Subgroup analyses revealed 18 loci associated with VT recurrence, with notable differences between pulmonary embolism (PE) and deep vein thrombosis (DVT). For example, the exonic variant SLC4A1 p.Glu40Lys was significantly associated with recurrence in PE patients (Hazard Ratio (HR)=3.23, P=9.7×10-12) but showed no effect in DVT (HR=1.00, P=0.98). These findings emphasize the role of specific genetic loci and protein pathways in influencing VT recurrence and provide valuable insights into potential therapeutic targets. Further research is needed to clarify the biological mechanisms driving these associations.

Identification of outcomes in clinical studies of interventions for venous thromboembolism in non‐pregnant adults

Venous Thromboembolism (VTE) Recurrence in Patients with Recurrent/Metastatic Solid Cancer Receiving Anticoagulation Therapy After Index VTE; Findings From Korean VTE Registry,

D-dimer testing after anticoagulant discontinuation to predict recurrent venous thromboembolism

Value of D-dimer testing to decide duration of anticoagulation after deep vein thrombosis: not yet.

Background/Introduction Cancer is a strong risk factor for the development of venous thromboembolism (VTE) including pulmonary embolism (PE) and deep vein thrombosis (DVT). Patients with VTE have a long-term risk of recurrence, which can be prevented by anticoagulation therapy. Prolonged anticoagulation therapy is recommended for patients with cancer-associated VTE, although the risk of recurrence might depend on the individual patient. Purpose We aimed to identify the risk factors of recurrence in patients with cancer-associated VTE. Methods The COMMAND VTE Registry is a multicenter retrospective registry enrolling 3027 consecutive patients with acute symptomatic VTE among 29 Japanese centers between January 2010 and August 2014. The present study population consisted of 695 cancer-associated VTE patients. The primary outcome measure in the present study was recurrent VTE, which was defined as PE and/or DVT with symptoms accompanied by confirmation of a new thrombus or exacerbation of the thrombus by objective imaging examinations or autopsy. Discontinuation of anticoagulation was defined as a withdrawal of anticoagulation therapy lasting &amp;gt;14 days for any reason. We selected clinically relevant variables and variables with P values &amp;lt;0.1 in a univariate analysis as potential risk factors, and constructed a multivariable Cox proportional hazard model for recurrent VTE incorporating the anticoagulation therapy status as a time-updated covariate. Results Among the 695 study patients, recurrent VTE occurred in 78 patients, of whom 54 (69%) occurred within 6 months. The cumulative incidence of recurrent VTE was 7.7% at 3-months, 8.9% at 6-months, 11.8% at 1-year, and 17.7% at 5-years. The cumulative incidence of discontinuation of anticoagulation therapy was 18.0% at 3-months, 29.5% at 6-months, 43.4% at 1-year, and 66.5% at 5-years. The cumulative 5-year incidence of recurrent VTE was most frequent in patients with uterus/ovary cancer (26.0%), followed by those with lung cancer (24.7%). The multivariable Cox proportional hazard model revealed that chronic kidney disease (HR, 2.27; 95% CI, 1.36–3.77, P=0.002), a high D-dimer level at the time of VTE diagnosis (HR, 2.85; 95% CI, 1.71–4.74, P&amp;lt;0.001), advanced cancer (HR, 1.69; 95% CI, 1.05–2.72, P=0.03) and discontinuation of anticoagulation therapy (HR, 2.66; 95% CI, 1.53–4.63, P&amp;lt;0.001) were independently associated with an increased risk of recurrent VTE. No cancer site was independently associated with an increased risk for recurrent VTE when adjusting for the above mentioned risk factors in the multivariable Cox proportional hazard model, although the risk of recurrent VTE numerically differed according to the cancer site. Conclusions Among patients with cancer-associated VTE, chronic kidney disease, a high D-dimer level at the time of VTE diagnosis, advanced cancer, and discontinuation of anticoagulation therapy were independent risk factors of recurrence. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Research Institute for Production Development, Mitsubishi Tanabe Pharma Corporation Figure 1Figure 2

Fixed-dose low-molecular-weight heparin, bemiparin, in the long-term treatment of venous thromboembolism in patients with transient risk factors in standard clinical practice: the FLEBUS study.

Thromb Haemost 2009; 101: 5–6 Venous thromboembolism (VTE) is a serious clinical condition manifesting as deep venous thrombosis (DVT) and/or pulmonary embolism (PE). Patients with VTE have a considerable risk of recurrent VTE that persists for many years (1, 2). In a population based cohort study, Heit et al. (1) found an overall cumulative percentage of VTE recurrence at 180 days, 1 and 10 years of 10.1%, 12.9%, and 30.4%, respectively. In another recent prospective cohort study, Prandoni et al. (2) reported, in patients with a first episode of VTE followed for eight years after oral anticoagulant therapy (OAT) withdrawal, a cumulative incidence of recurrence of 17.5% after two years, 24.6% after five years, and 30.3% after eight years. OAT is effective in reducing the VTE recurrence rate. However, anticoagulant treatment is associated with an increased risk for bleeding complications (3). Thus, anticoagulation has to be discontinued when the benefit of treatment no longer outweighs its risks and this clearly depends on the estimated risk of recurrence. The optimal duration of OAT is established, either after a first episode of VTE, in patients with a transient or with a persistent risk factor for VTE with an average risk of bleeding. Patients with a persistent risk factor for VTE had a high risk of recurrence. In patients with cancer, the risk of recurrent VTE after stopping anticoagulant therapy is as high as 10% to 20% in the first year, particularly among those with metastatic disease or among those who received concurrent chemotherapy (2, 4). Thus, in view of the persistently high risk of VTE recurrence, a prolonged anticoagulant treatment is currently recommended in patients as long as the cancer remains active. Conversely, in patients with major reversible risk factor such as surgery, immobilization or trauma, the risk of recurrence is relatively low (5), and to stop anticoagulant therapy after three months of treatment appears to be a reasonable option. On the other hand, the optimal duration of OAT in patients with a first unprovoked episode of VTE is still uncertain, and recent guidelines of the American College of Chest Physician suggested to carefully assess the potential risks and benefits of long-term OAT in each patient (6). Recently, several studies have assessed the role of some individual features evaluated at the end of conventional anticoagulant treatment as risk factors for recurrence (7, 8). The main aim of this approach was to identify those patients with unprovoked VTE who could benefit from extended anticoagulant treatment. In a randomized controlled study, Palareti et al. showed that patients one month after discontinuation of anticoagulation with an abnormal D-dimer level had a significantly higher incidence of recurrent VTE compared to patients with normal D-dimer, and that resumption of anticoagulation was effective in reducing thromboembolic complications in these patients (7). In a prospective cohort study on 313 consecutive symptomatic outpatients with proximal DVT, Prandoni et al. showed that persistence of residual venous thrombosis at follow-up visits was associated with an increased risk VTE recurrence (8). Several studies and a meta-analysis have revealed that men have at higher risk of recurrence than women (9) and first manifestation of thrombosis as PE seems to be associated with an increased risk of VTE recurrence (10). During the last decade several abnormalities in the coagulation system have been shown to be associated with an increased risk of thrombosis. Their impact on the recurrence rate has been the focus of several clinical studies. Factor V Leiden and the prothrombin G20210A variation, the commonest inherited risk factors for thrombosis, are associated with an increased risk of VTE recurrence (11). However, the magnitude of the risk conferred by the presence of one of these risk factors is modest and not sufficient to warrant long-term anticoagulation. Inherited deficiencies of natural anticoagulants antithrombin, protein C, and protein S are present in less than 10% of VTE patients (12). Patients with these deficiencies are considered at higher risk for VTE (13). On the other hand, only few studies with a limited number of included patients have assessed the risk of recurrence associated with these thrombophilic abnormalities (14, 15). In these studies, the risk of recurrence in patients with first VTE and a thrombophilic defect and in patients without a thrombophilic defect was similar. However, these studies also included patients with other thrombophilic defects such as factor V Leiden, prothrombin G20210A mutation and included a relatively small number of patients with deficiencies of natural anticoagulants.

Association between initial and residual pulmonary vascular obstruction and pulmonary embolism recurrence, a pooled analysis

Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH

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

Risk Factors Associated with 6-Month Recurrent VTE Among Patients in Two Large Population-Based Surveillance Systems

Apolipoprotein M and the risk of unprovoked recurrent venous thromboembolism

The Incidence, Risk Factors, and Prognosis of Recurrent Venous Thromboembolism (VTE) in Patients with Advanced Solid Cancers Receiving Anticoagulation Therapy After the Diagnosis of Index Vte; A Korean Venous Thromboembolism Registry Study.

The British Committee for Standards in Haematology (BCSH) published its third edition of Guidelines on Oral Anticoagulation in 1998 (British Committee for Standards in Haematology, 1998). Most of the recommendations made in 1998 remain unchanged and a fourth edition of the guideline is considered unnecessary at the time of writing (June 2005). However, we draw attention to those areas where new informative data have been published. As in the original guideline, the term ‘oral anticoagulant’ used in this update refers to oral vitamin K antagonists (VKA), such as warfarin. New oral non-VKA are currently being evaluated in clinical trials but are not yet licensed for use in the UK. When these drugs become available new guidance will be issued specifically for the use of those drugs. The guideline group was selected to be representative of UKbased medical experts. The drafting group met and communicated by email. MEDLINE was searched systematically for publications in English from 1998. The writing group convenor (T. Baglin) produced the draft guidelines which were subsequently revised by consensus. The guideline was reviewed by a multidisciplinary sounding board, the BCSH and the British Society for Haematology (BSH) and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are as in Appendix 3 of the Procedure for Guidelines Commissioned by the BCSH (http://www.bcshguidelines.com/process1.asp#App3). The target audience for this guideline is healthcare professionals involved in the management of patients receiving oral anticoagulant therapy.