Increased Risk Of Venous Thromboembolism Research Articles

Hemostasis at Extremes of Body Weight.

Extremes of body weight are not uncommon in the modern world and include anorexia nervosa (AN) and obesity. Both conditions are associated with increased morbidity and mortality: AN has the highest mortality rate of all mental illnesses and unfortunately obesity has reached epidemic proportions and is a well-recognized risk factor for cardiovascular disease including venous thromboembolism (VTE). This article summarizes the current understanding of hemostatic changes of these extremes of body weight. The hemostatic changes of AN have not been well described. Severe AN is associated with pancytopenia with decreased bone marrow cellularity, which causes a mild thrombocytopenia. Platelet hyperaggregability has been recognized in AN and has been attributed at least in part to increased adrenoceptor density. Obesity and the metabolic syndrome are associated with prothrombotic changes, which have been well characterized and related to complex adipocyte-induced inflammatory changes, including increased levels of plasminogen activator inhibitor type 1, von Willebrand factor, fibrinogen, and other evidence of increased coagulation and platelet activation. Accumulating evidence suggests a significant role for increased tissue factor expression and signaling in this relationship, with increased tissue factor expression present in adipose and possibly systemic tissues, induced by adipose-generated cytokines. Intriguingly, the hemostatic changes do not seem to increase with increasing BMI, although the risk of VTE increases with BMI, suggesting that decreased venous flow due to venous enlargement may play the most important role in increased VTE risk with obesity.

Real-world features associated with cancer-related venous thromboembolic events

BackgroundThe incidence of venous thromboembolism (VTE) is 1–2/1000 individuals. Patients with cancer, especially during chemotherapy, are at enhanced risk, but real-world data on factors associated with VTE events are still scarce.AimThe aim of this retrospective study was to survey the incidence of VTE based on a large hospital database, and to identify comorbidities and features associated with VTE events. We focused on cancer-related VTE events and on factors indicating increased VTE risk during chemotherapy.MethodsThe cohort included patients treated at Turku University Hospital during years 2005–2013. Health information was derived and analysed from multiple electronic databases. The diagnoses of VTE and all comorbidities, including type of cancer, were based on International Classification of Diseases 10th Revision coding. For further analysis, we focused on 16 common types of cancers treated with chemotherapy. Age, gender, surgery, radiotherapy, distant metastasis, available laboratory values and platinum-based chemotherapy were evaluated for VTE group, and associations were estimated by Cox regression analyses.ResultsThe entire database contained information from 495 089 patients, of whom 5452 (1.1%) had a VTE diagnosis. Among individuals with VTE, 1437 (26.4%) had diagnosis of coronary heart disease and 1467 (26.9%) had cancer diagnosis. Among 7778 patients with cancer treated with chemotherapy, 282 (3.6%) had a VTE, platinum-based chemotherapy being a major risk factor (HR 1.77, 95% CI 1.40 to 2.24, p<0.001). In multivariate analysis, elevated blood neutrophil counts (>3.25×109 cells/L, HR 1.96, 95% CI 1.33 to 2.89, p<0.001) and plasma creatinine (>62.5 μmol/L; HR 1.60, 95% CI 1.21 to 2.13, p=0.001) values were independent indicators of increased VTE risk during chemotherapy.ConclusionsLongitudinal electronic health record analysis provides a powerful tool to gather meaningful real-world information to study clinical associations, like comorbidities, and to identify markers associated with VTE. The combination of various clinical and laboratory variables could be used for VTE risk evaluation and targeted prevention.

Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: A systematic review and meta-analysis

IntroductionHormone therapy (HT) is an effective treatment for climacteric symptoms. Nevertheless, combined estrogen-progestin therapy and the oral route seem to entail higher risk of venous thromboembolism (VTE) than estrogen-only therapy and transdermal administration. The present study aimed to investigate the risk of thromboembolic events in postmenopausal women using non-oral estrogen compared to women using oral estrogen and control groups (women receiving placebo or non-users of HT), as well as to assess the thrombotic impact of estrogens alone vs. combined estrogen-progestin therapy. Materials and methodsSystematic review of MEDLINE, Cochrane CENTRAL, EMBASE, and ClinicalTrials.gov according to PRISMA guidelines. ResultsTwenty-two studies were included in the meta-analyses (9 case-control studies, 9 cohort studies, and 4 randomized controlled trials). As compared to control groups, VTE risk was not increased with non-oral HT, including users of estrogens and estrogens plus progestins (OR 0.97 [0.9–1.06]), non-oral estrogen therapy (ET)-only (OR 0.95 [0.81–1.10]), and non-oral combined estrogen-progestin therapy (OR 0.92 [0.77–1.09]). Conversely, increased risk of VTE was observed as compared with control groups in users of oral HT, including users of estrogens and estrogens plus progestins HT (OR 1.72 [1.47–2.01]), oral ET-only (OR 1.43 [1.34–1.53]), and combined oral estrogen-progestin HT (OR 2.35 [1.9–2.9]). The comparison of non-oral vs. oral HT showed increased VTE risk with oral HT (OR 1.66 [1.39–1.98]). ConclusionsVTE risk was increased in postmenopausal women with no previous thromboembolic events using oral HT. Non-oral HT did not significantly affect this risk. The quality of the evidence produced in our meta-analyses is low to moderate, and further clinical trials are needed to sort out the impact of different types of progestin and different estrogen doses and administration routes on VTE risk.

Combination of isocitrate dehydrogenase 1 (IDH1) mutation and podoplanin expression in brain tumors identifies patients at high or low risk of venous thromboembolism

Essentials Risk stratification for venous thromboembolism (VTE) in patients with brain tumors is challenging.Patients with IDH1 wildtype and high podoplanin expression have a 6‐month VTE risk of 18.2%.Patients with IDH1 mutation and no podoplanin expression have a 6‐month VTE risk of 0%. IDH1 mutation and podoplanin overexpression in primary brain tumors appear to be exclusive. SummaryBackgroundVenous thromboembolism (VTE) is a frequent complication in primary brain tumor patients. Independent studies revealed that podoplanin expression in brain tumors is associated with increased VTE risk, whereas the isocitrate dehydrogenase 1 (IDH1) mutation is associated with very low VTE risk.ObjectivesTo investigate the interrelation between intratumoral podoplanin expression and IDH1 mutation, and their mutual impact on VTE development.Patients/MethodsIn a prospective cohort study, intratumoral IDH1 R132H mutation and podoplanin were determined in brain tumor specimens (mainly glioma) by immunohistochemistry. The primary endpoint of the study was symptomatic VTE during a 2‐year follow‐up.ResultsAll brain tumors that expressed podoplanin to a medium‐high extent showed also an IDH1 wild‐type status. A score based on IDH1 status and podoplanin expression levels allowed prediction of the risk of VTE. Patients with wild‐type IDH1 brain tumors and high podoplanin expression had a significantly increased VTE risk compared with those with mutant IDH1 tumors and no podoplanin expression (6‐month risk 18.2% vs. 0%).Conclusions IDH1 mutation and podoplanin overexpression seem to be exclusive. Although brain tumor patients with IDH1 mutation are at very low risk of VTE, the risk of VTE in patients with IDH1 wild‐type tumors is strongly linked to podoplanin expression levels.

The Role of Inflammation in Venous Thromboembolism.

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT), and pulmonary embolism (PE), is becoming increasingly recognized as a cause of morbidity and mortality in pediatrics, particularly among hospitalized children. Furthermore, evidence is accumulating that suggests the inflammatory response may be a cause, as well as consequence, of VTE, but current anticoagulation treatment regimens are not designed to inhibit inflammation. In fact, many established clinical VTE risk factors such as surgery, obesity, cystic fibrosis, sepsis, systemic infection, cancer, inflammatory bowel disease, and lupus likely modulate thrombosis through inflammatory mediators. Unlike other traumatic mechanisms of thrombosis involving vascular transection and subsequent exposure of subendothelial collagen and other procoagulant extracellular matrix materials, inflammation of the vessel wall may initiate thrombosis on an intact vein. Activation of endothelial cells, platelets, and leukocytes with subsequent formation of microparticles can trigger the coagulation system through the induction of tissue factor (TF). Identification of biomarkers to evaluate VTE risk could be of great use to the clinician caring for a patient with inflammatory disease to guide decisions regarding the risk:benefit ratio of various types of potential thromboprophylaxis strategies, or suggest a role for anti-inflammatory therapy. Unfortunately, no such validated inflammatory scoring system yet exists, though research in this area is ongoing. Elevation of C-reactive protein, IL-6, IL-8, and TNF-alpha during a response to systemic inflammation have been associated with increased VTE risk. Consequent platelet activation enhances the prothrombotic state, leading to VTE development, particularly in patients with other risk factors, most notably central venous catheters.

PCV47 - Extended Thromboprophylaxis With Betrixaban Is Cost-Effective In Acutely ILL Medical Patients

The APEX trial demonstrated that prophylaxis of venous thromboembolism (VTE) with betrixaban from hospital admission through post-discharge (35-42 days) in acutely ill medical patients reduced VTE events without significant increase in major bleeding vs standard-duration prophylaxis (6-14 days) with enoxaparin. Here, we analyzed the cost-effectiveness of this new thromboprophylaxis regimen with betrixaban versus standard-duration enoxaparin. We adopted our previously published decision-tree model to compare two thromboprophylaxis strategies from a US health care provider perspective among a hypothetical cohort of 10,000 acutely ill medical patients who are at risk of VTE: betrixaban (160 mg loading dose followed by 80 mg once daily for 35 days; $396) versus enoxaparin (40 mg daily for 9 days; $284). To estimate VTE-related deaths within 35 days that might have been averted by thromboprophylaxis, the model incorporated a clinical care path, including primary and secondary VTE prophylaxis as well as treatment of thromboprophylaxis-related adverse events. Parameter values and costs were estimated for each node in the decision tree based on publically available health data. All costs were converted to 2017 USD based on the US medical care consumer index. For the base-case scenario, among a hypothetical cohort of 10,000 acutely ill medical patients at increased VTE risk, betrixaban was estimated to reduce risk of death by 0.16% and save nearly $1.8M (or $178.27 per patient treated). One-way sensitivity analyses indicated that betrixaban would dominate enoxaparin assuming: a) the cost of 35-day betrixaban was <$15.94 per dose (<$574 per 36 doses); b) the clinically relevant recognized bleeding rate was ≤3.8% or c) the VTE rate was ≤7.2%. Based on the rates of clinical events reported in the APEX study, thromboprophylaxis with betrixaban from admission through post-discharge in acutely ill medical patients is likely to prevent additional deaths and reduce costs compared with standard-duration thromboprophylaxis with enoxaparin.

Pharmacological properties of betrixaban.

Venous thromboembolism (VTE) in acute medically ill patients is a leading cause of in-hospital morbidity and mortality. A majority of these VTE events occur post-discharge, and patients remain at increased VTE risk for up to 3 months post-discharge. Recent clinical trials of extended-duration thromboprophylaxis with enoxaparin, rivaroxaban, and apixaban in acute medically ill patients did not demonstrate a net clinical benefit compared with in-hospital thromboprophylaxis, and were shown to be associated with higher risks of major bleeding. Betrixaban is a new direct oral anticoagulant (DOAC) with a different pharmacokinetic profile than other DOACs. Betrixaban has the longest half-life among the DOAC class, with a terminal half-life of 35–45 h and an effective half-life of 19–27 h. Betrixaban has a low peak-to-trough ratio compared with other anticoagulants and a predictable duration of drug exposure, leading to overall consistent anticoagulant effect over 24 h. Betrixaban is mainly cleared via the hepatobiliary system and therefore not contraindicated in patients with severe renal insufficiency. Betrixaban was recently approved for the indication of extended thromboprophylaxis in the United States based on the APEX trial of betrixaban 80 mg once daily for 35–42 days compared with low molecular weight heparin enoxaparin for 10 ± 4 days in hospitalized acute medically ill patients. This study demonstrated that extended-duration betrixaban reduced VTE compared with standard-duration enoxaparin in acute medically ill patients, without increased risk of major bleeding. This patient population at risk of VTE may benefit from extended prophylaxis, ensuring continuum of care from in-hospital to post-discharge.

Risk of venous thromboembolism in patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

Background: Recent studies have suggested that patients with idiopathic pulmonary fibrosis (IPF) may have a higher risk of venous thromboembolism (VTE) compared to general population even though the results were inconsistent. Objective: To investigate the risk of VTE among patients with IPF. Methods: Comprehensive literature review using MEDLINE and EMBASE database were performed to identify studies that compared the risk of VTE among patients with IPF to general population. Effect estimates from each study were combined together using random effect model, generic inverse variance method of DerSimonian and Laird. Results: Out of 510 retrieved articles, 5 studies met the inclusion criteria and were included in the meta-analysis. A significant risk of VTE in patients with IPF was observed with the pooled risk ratio of 2.11 (95% confidence interval, 1.28-3.48). The heterogeneity was moderate with I2 of 64%. Conclusion: An approximately 2-fold increased risk of VTE among patients with IPF was observed in this meta-analysis. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 109-114).

The role of podoplanin in cancer-associated thrombosis

Venous thromboembolism (VTE) is a frequent and life-threatening complication in patients with cancer. The underlying mechanisms of cancer-associated VTE are still not completely understood. However, emerging studies indicate that the mechanisms differ across tumor types. A recent study revealed that in patients with brain tumors, podoplanin overexpression is strongly correlated with intratumoral thrombotic vessels, hypercoagulability and increased VTE risk. In vitro experiments demonstrated that platelet aggregation induced by human glioblastoma cells was highly podoplanin-dependent.Podoplanin is a transmembrane glycoprotein with the ability to induce platelet activation via the platelet-receptor CLEC-2. Moreover, podoplanin is a lymphatic endothelial marker and exhibits substantial functions during embryonic development. It is variously upregulated by many cancers including primary brain tumors and linked to malignant progression and poor survival. In vivo studies have indicated that the podoplanin-CLEC-2 axis might be mechanistically involved in the development of venous thrombosis.In this review, we discuss the role of podoplanin in promoting cancer-associated VTE. Since podoplanin is associated with VTE risk in brain tumor patients, it could be a useful biomarker to identify patients at very high VTE risk. Those patients may benefit from primary thromboprophylaxis. In addition, the podoplanin-CLEC-2 axis might serve as an attractive target for new therapies against cancer-associated VTE.

Abstract 135: Extended Thromboprophylaxis With Betrixaban is Cost-effective in Acutely Ill Medical Patients

Objectives: The APEX trial demonstrated that prophylaxis of venous thromboembolism (VTE) with betrixaban from hospital admission through post-discharge (35-42 days) in acutely ill medical patients reduced VTE events, including symptomatic VTEs, without significant increase in major bleeding versus standard-duration prophylaxis (6-14 days) with enoxaparin. Based on these data, betrixaban has been approved by the FDA for prophylaxis of VTE in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications. Here, we analyzed the cost-effectiveness of this new thromboprophylaxis regimen with betrixaban versus standard-duration thromboprophylaxis with enoxaparin. Methods: We adopted our previously published decision-tree model to compare two thromboprophylaxis strategies from a US health care provider perspective among a hypothetical cohort of 10,000 acutely ill medical patients who are at risk of VTE: betrixaban (160 mg loading dose followed by 80 mg once daily for 35 days; $396) versus enoxaparin (40 mg daily for 9 days; $284). To estimate VTE-related deaths within 35 days that might have been averted by thromboprophylaxis, the model incorporated a clinical care path, including primary and secondary VTE prophylaxis as well as treatment of thromboprophylaxis-related adverse events. Parameter values and costs were estimated for each node in the decision tree based on publically available health data. All costs were converted to 2017 USD based on the US medical care consumer index. Results: For the base-case scenario, among a hypothetical cohort of 10,000 acutely ill medical patients at increased VTE risk, betrixaban was estimated to reduce risk of death by 0.16% and save nearly $1.8M (or $178.27 per patient treated). One-way sensitivity analyses indicated that betrixaban would dominate enoxaparin assuming: a) the cost of 35-day betrixaban was &lt;$15.94 per dose (&lt;$574 per 36 doses); b) the clinically relevant recognized bleeding rate was ≤3.8% or c) the VTE rate was ≤7.2%. Conclusions: Based on the rates of clinical events reported in the APEX study, extended-duration thromboprophylaxis with betrixaban from hospital admission through post-discharge in acutely ill medical patients is likely to prevent additional deaths and reduce costs compared with standard-duration thromboprophylaxis with enoxaparin.

Systematic review and meta-analysis of the association of combined oral contraceptives on the risk of venous thromboembolism: The role of the progestogen type and estrogen dose

IntroductionCurrently available combined oral contraceptives (COC) reportedly increase the risk of venous thromboembolism (VTE). We aimed to quantify this risk considering both progestogen type and estrogen dose. Materials and methodsPubMed, Embase and LIVIVO were searched for relevant publications until April 2017. Case-control and cohort studies including healthy women taking COC and assessing incident VTE as outcome were selected. Adjusted relative risks (RR) with 95% confidence intervals (CI) derived from random effects model using a generic inverse-variance approach are reported. ResultsOverall, 1,359 references were identified and 17 studies were included in the meta-analysis. The pooled RR of VTE was associated with various COC, with the association depending on their respective estrogen dose and progestogen type. Compared to the reference, levonorgestrel with 30–40 μg ethinylestradiol, the overall risk of VTE was higher for all other COC. Preparations with desogestrel with 30–40 μg estrogen showed the highest relative risk (RR: 1.46; 95% CI: 1.33–1.59), while RRs for drospirenone (30–40 μg ethinylestradiol) and desogestrel (30–40/20 μg ethinylestradiol) were lower. COC containing gestodene and cyproterone with 30–40 μg estrogen showed the lowest risk (RR: 1.27; 95% CI: 1.15–1.41 and RR: 1.29; 95% CI: 1.12–1.49, respectively). ConclusionsCompared to levonorgestrel with 30–40 μg ethinylestradiol, all COC showed a significantly increased VTE risk. The association varied depending on the progestogen type and the dose of estrogen. Our results suggest that the prescription of COC with the lowest possible dose of ethinylestradiol may help to avoid VTE cases among young, healthy women.

Obesity and risk for venous thromboembolism from contemporary therapy for pediatric acute lymphoblastic leukemia

IntroductionAcute lymphoblastic leukemia (ALL) therapy confers risk for venous thromboembolism (VTE) and associated acute and long-term morbidity. Obesity increases VTE risk in the general population but its impact on ALL therapy-associated VTE is unknown. MethodsIn a retrospective cohort of children treated for ALL between 2008 and 2016 (n = 294), we analyzed obesity at diagnosis (body mass index [BMI] ≥95%) and subsequent development of VTE. A subset participated in two concurrent prospective ALL trials studying body composition via dual-energy X-ray absorptiometry (DXA) (n = 35) and hypercoagulability via thromboelastography (TEG) (n = 46). Secondary analyses explored whether precise measurement of body fat and/or global hemostasis ex vivo by TEG could further delineate VTE risk in the obese. ResultsOverall, we found 27/294 (9.2%) patients developed symptomatic VTE during therapy, 19/27 (70%) occurred during Induction. Study-defined “serious” VTE developed in 4/294 (1.4%) of patients. Obesity but not overweight was strongly predictive of symptomatic VTE (obesity odds ratio = 3.8, 95% confidence interval 1.5–9.6, p = 0.008). In the DXA subset, only 2/35 patients developed symptomatic VTE. However, within those prospectively screened during Induction, 30% (14/46) developed VTE; eight (17%) of these were asymptomatic and found only via screening. ConclusionsIn this pediatric ALL cohort, obesity conferred more than a three-fold increased risk for symptomatic VTE. In a subgroup of patients who underwent active screening, up to a third were noted to have VTE (symptomatic and asymptomatic). TEG did not predict VTE. Additional studies are necessary to validate these findings and to further refine a risk-stratified approach to thrombo-prevention during ALL therapy.

Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients

Background Neutrophil extracellular traps (NETs) are decondensed chromatin fibers that might play a role in the prothrombotic state of cancer patients. Objectives To investigate whether the levels of citrullinated histone H3 (H3Cit), a biomarker for NET formation, cell-free DNA (cfDNA) and nucleosomes predict venous thromboembolism (VTE) in cancer patients. Patients/Methods Nine-hundred and forty-six patients with newly diagnosed cancer or progression after remission were enrolled in this prospective observational cohort study. H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients were followed for 2 years. VTE occurred in 89 patients; the cumulative 3-month, 6-month, 12-month and 24-month incidence rates of VTE were 3.7%, 6.0%, 8.1%, and 10.0%, respectively. Results Patients with elevated H3Cit levels (> 75th percentile of its distribution, n = 236) experienced a higher cumulative incidence of VTE (2-year risk of 14.5%) than patients with levels below this cut-off (2-year risk of 8.5%, n = 710). In a competing-risk regression analysis, a 100 ng mL-1 increase in H3Cit level was associated with a 13% relative increase in VTE risk (subdistribution hazard ratio [SHR] 1.13, 95% confidence interval [CI] 1.04-1.22). This association remained after adjustment for high VTE risk and very high VTE risk tumor sites, D-dimer level, and soluble P-selectin level (SHR 1.13, 95% CI 1.04-1.22). The association of elevated nucleosome and cfDNA levels with VTE risk was time-dependent, with associations with a higher risk of VTE only during the first 3-6 months. Conclusion These data suggest that biomarkers of NET formation are associated with the occurrence of VTE in cancer patients, indicating a role of NETs in the pathogenesis of cancer-associated thrombosis.

A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception.

BackgroundCombined oral contraceptives (COCs) containing various progestogens could be associated with differential risks for venous thromboembolism (VTE).ObjectiveTo evaluate the comparative risks of VTE associated with the use of low‐dose (less than 50 μg ethinyl estradiol) COCs containing different progestogens.Search strategyPubMed and the Cochrane Library were searched from database inception through September 15, 2016, by combining search terms for oral contraception and venous thrombosis.Selection criteriaStudies reporting VTE risk estimates among healthy users of progestogen‐containing low‐dose COCs were included.Data collection and analysisA random‐effects model was used to generate pooled adjusted risk ratios and 95% confidence intervals; subgroup and sensitivity analyses assessed the impact of monophasic‐COC use and study‐level characteristics.Main resultsThere were 22 articles included in the analysis. The use of COCs containing cyproterone acetate, desogestrel, drospirenone, or gestodene was associated with a significantly increased risk of VTE compared with the use of levonorgestrel‐containing COCs (pooled risk ratios 1.5–2.0). The analysis restricted to monophasic COC formulations with 30 μg of ethinyl estradiol yielded similar findings. After adjustment for study characteristics, the risk estimates were slightly attenuated.ConclusionsCompared with the use of levonorgestrel‐containing COCs, the use of COCs containing other progestogens could be associated with a small increase in risk for VTE.

TV viewing and incident venous thromboembolism: the Atherosclerotic Risk in Communities Study.

TV viewing is associated with risk of arterial vascular diseases, but has not been evaluated in relation to venous thromboembolism (VTE) risk in Western populations. In 1987-1989, the Atherosclerosis Risk in Communities Study obtained information on the frequency of TV viewing in participants aged 45-64 and followed them prospectively. In individuals free of prebaseline VTE (n = 15, 158), we used a Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident VTE according to frequency of TV viewing ("Never or seldom", "Sometimes", "Often" or "Very often"). During the 299,767 person-years of follow-up, we identified 691 VTE events. In a multivariable-adjusted model, the frequency of TV viewing showed a positive dose-response relation with VTE incidence (P for trend = 0.036), in which "very often" viewing TV carried 1.71 (95% CI 1.26-2.32) times the risk of VTE compared with "never or seldom" viewing TV. This association to some degree was mediated by obesity (25% mediation, 95% CI 10.7-27.5). Even among individuals who met a recommended level of physical activity, viewing TV "very often" carried 1.80 (1.04-3.09) times the risk of VTE, compared to viewing TV "never or seldom". Greater frequency of TV viewing was independently associated with increased risk of VTE, partially mediated by obesity. Achieving a recommended physical activity level did not eliminate the increased VTE risk associated with frequent TV viewing. Avoiding frequent TV viewing as well as increasing physical activity and controlling body weight might be beneficial for VTE prevention.

α2-Macroglobulin Is a Significant In Vivo Inhibitor of Activated Protein C and Low APC:α2M Levels Are Associated with Venous Thromboembolism.

Activated protein C (APC) is a major regulator of thrombin formation. Two major plasma inhibitors form complexes with APC, protein C inhibitor (PCI) and α1-antitrypsin (α1AT), and these complexes have been quantified by specific enzyme-linked immunosorbent assays (ELISAs). Also, complexes of APC with α2-macroglobulin (α2M) have been observed by immunoblotting. Here, we report an ELISA for APC:α2M complexes in plasma. Plasma samples were pre-treated with dithiothreitol and then with iodoacetamide. The detection range of the newly developed APC:α2M assay was 0.031 to 8.0 ng/mL of complexed APC. Following infusions of APC in humans and baboons, complexes of APC with α2M, PCI and α1AT were quantified. These complexes as well as circulating APC were also measured in 121 patients with a history of venous thromboembolism (VTE) and 119 matched controls. In all the in vivo experiments, α2M was a significant APC inhibitor. The VTE case-control study showed that VTE patients had significantly lower APC:α2M and APC levels than the controls (p < 0.001). Individuals in the lowest quartile of APC:α2M or the lowest quartile of APC had approximately four times more VTE risk than those in the highest quartile of APC:α2M or of APC. The risk increased for individuals with low levels of both parameters. The APC:α2M assay reported here may be useful to help monitor the in vivo fate of APC in plasma. In addition, our results show that a low APC:α2M level is associated with increased VTE risk.

179 - Lenalidomide Exposure Prior to Autologous Stem Cell Transplantation May Increase Risk of Venous Thromboembolism (VTE) in Patients with Multiple Myeloma (MM)

179 - Lenalidomide Exposure Prior to Autologous Stem Cell Transplantation May Increase Risk of Venous Thromboembolism (VTE) in Patients with Multiple Myeloma (MM)

Joint effects of prothrombotic genotypes and body height on the risk of venous thromboembolism: the Tromsø study

Background Studies have reported synergistic effects of prothrombotic single-nucleotide polymorphisms (SNPs) and obesity on the risk of venous thromboembolism (VTE). Tall stature is associated with an increased VTE risk, but the joint effect of prothrombotic genotypes and tall stature on the VTE risk is unknown. Aims To investigate the joint effects of prothrombotic genotypes and tall stature on the VTE risk. Methods Cases with incident VTE (n=676) and a randomly selected age-weighted subcohort (n=1842) were sampled from the Tromsø study (cohort follow-up: 1994-2012). DNA was genotyped for rs6025 (factorV Leiden), rs1799963 (FII), rs8176719 (ABO blood group), rs2066865 (fibrinogen-γ), and rs2036914 (FIX). Age-adjusted and sex-adjusted hazard ratios (HRs) of VTE were calculated by categories of risk alleles (de Haan 5-SNP score: 0-1, 2-3, and ≥4) and body height (<40th, 40th-80th and >80th percentiles). Results The VTE risk increased by increasing category of body height, and subjects with height ≥178cm had a two-fold higher VTE risk (HR2.03; 95% confidence interval [CI]1.51-2.73) than those with height ≤165cm. The VTE risk also increased across categories of risk alleles. However, the combination of a tall stature and risk alleles, either individual SNPs or risk score, did not result in an excess VTE risk. Subjects with four or more risk alleles and height ≥178cm had a two-fold (HR2.08; 95%CI1.24-3.52) higher VTE risk than subjects ≤165cm with no risk allele or one risk allele. Conclusions In contrast to obesity, the presence of prothrombotic genotypes did not result in an excess VTE risk in subjects with a tall stature.

Comparison of acute and convalescent biomarkers of inflammation in patients with acute pulmonary embolism treated with systemic fibrinolysis vs. placebo.

: Previous studies have associated biomarkers indicative of acute inflammation with pulmonary embolism, which may amplify coagulation, inhibit fibrinolysis and increase risk of venous thromboembolism (VTE) recurrence. The aim of this study was to measure inflammatory and hemostatic biomarkers in acute submassive pulmonary embolism at diagnosis and 3-month follow-up and to test the impact of treatment with fibrinolysis. Secondary analysis of a multicenter, double-blinded, randomized controlled trial including patients with submassive pulmonary embolism. Blood samples were obtained within 24 h of diagnosis and prior to bolus-dose tenecteplase (TNK) or placebo; all patients received standard anticoagulation and blood was redrawn 3 months later. Plasma concentrations of inflammatory [Interleukin 6 (IL-6), C-reactive protein (CRP), myeloperoxidase (MPO)] and hemostatic [plasminogen activator inhibitor-1 (PAI-1), fibrinogen, thrombin-activatable fibrinolysis inhibitor and D-dimer] biomarkers were quantified. The median values of the biomarkers of inflammation (IL-6, CRP, MPO) were all significantly decreased at 3-month follow-up, ranging from a 60 to 91% reduction over this time period. Concentrations of PAI-1 and fibrinogen did not change significantly. D-dimer concentration at 3-month follow-up was lower in patients treated with fibrinolysis vs. placebo and appeared to have a trend toward significance (placebo 310 vs. TNK 220 ng/ml, P = 0.051). Acute pulmonary embolism causes marked but transient inflammation, as demonstrated by the significant elevation in the inflammatory biomarkers at diagnosis, followed by their reduction in more than 80% of patients at 3-month follow-up.

Improving venous thromboembolism risk assessment rates in a tertiary urology department.

Venous thromboembolism (VTE) is a significant cause of mortality and morbidity among hospitalised patients. A VTE risk assessment reduces this through facilitating correct prophylaxis. Since 2010, the Commissioning for Quality and Innovation payments framework dictates that >95% adult inpatients must have a VTE risk assessment within 24 hours of admission. This target is not currently being met by the urology department at Guy’s and St. Thomas’ Trust (GSTT). Following analysis, a quality improvement project aimed to increase VTE risk assessment rates for patients admitted under urology at GSTT. Two series of interventions were introduced following the Plan, Do, Study, Act structure aimed at urology theatres and wards, respectively. These boosted awareness of the VTE risk assessment and streamlined it into routine surgical workload. Despite not reaching the 95% target, the project increased rates among patients admitted directly to surgical units by 5%–8%. It highlighted the difficulties in driving a change in established routine and demonstrated a need for firmer interventions with effective communication.