Etiology Of Venous Thromboembolism Research Articles

Genetic associations of protein-coding variants in venous thromboembolism

Previous genetic studies of venous thromboembolism (VTE) have been largely limited to common variants, leaving the genetic determinants relatively incomplete. We performed an exome-wide association study of VTE among 14,723 cases and 334,315 controls. Fourteen known and four novel genes (SRSF6, PHPT1, CGN, and MAP3K2) were identified through protein-coding variants, with broad replication in the FinnGen cohort. Most genes we discovered exhibited the potential to predict future VTE events in longitudinal analysis. Notably, we provide evidence for the additive contribution of rare coding variants to known genome-wide polygenic risk in shaping VTE risk. The identified genes were enriched in pathways affecting coagulation and platelet activation, along with liver-specific expression. The pleiotropic effects of these genes indicated the potential involvement of coagulation factors, blood cell traits, liver function, and immunometabolic processes in VTE pathogenesis. In conclusion, our study unveils the valuable contribution of protein-coding variants in VTE etiology and sheds new light on its risk stratification.

Clinical Factors Associated with Catheter-Related VTE in Patients Undergoing Hematopoietic Cell Transplantation

Introduction: In patients undergoing allogeneic hematopoietic cell transplantation (HCT), venous thromboembolism (VTE) is associated with increased morbidity and worse survival. Central venous catheters (CVC) are placed for administration of both stem cell products and other supportive measures. CVC are a common etiology of VTE during HCT. This study examines the associations between patient- and CVC-related variables and the incidence of catheter-related thrombosis (CRT) in patients undergoing allogeneic HCT. Methods: We selected consecutive patients who underwent their first allogeneic HCT from MD Anderson Cancer Center between 2016-2020. The electronic medical records (EMR) of these patients were examined using ICD 9/10 codes, and radiology reports using a natural language processing (NLP) algorithm to look for VTE events. All VTE events were confirmed via manual chart review. Details on the type of CVC, anatomic venous location, laterality, and size were extracted. For this study, CVC was defined as a catheter that extends into the superior vena cava; these catheters were classified as either a peripherally induced central catheter (PICC), non-tunneled CVC, or tunneled CVC. Unadjusted and multivariable Cox proportional hazards models were used to assess the association between patient and transplant factors and time to CRT. Acute graft versus host disease and active infection were included in the models as categorical time varying covariates. Cumulative incidence competing risk model was used to assessed CRT incidence with death as a competing cause. Results: There were 1371 adult patients included in the study. Most patients had non-tunneled CVC as their central access, with the subclavian vein being the most used location (Table 1). A total of 207 patients had VTE during the first year post-HCT, with 153 having isolated CRT and 54 having other VTE (Table 1). The incidence of CRT was 7.7% at 100-day and 11.3% at 1-year, with the incidence rate at a near constant estimate in the first 100 days. The cumulative incidence of DVT/PE with death as a competing risk factor was 1.17% at 100-day and 4.08% at 1-year. In Cox regression models for CRT by 100 days, history of VTE, higher platelet count, acute GVH disease stage 3-4, and infection were statistically associated with time to CRT (Table 2). The type of CVC (non-tunneled CVC and PICC vs. tunneled CVC) was non-significantly associated with increased risk of CRT. Conclusion: In our cohort of patients undergoing allogeneic HCT, the incidence of CRT appeared to be higher than that reported in the literature. Significant risk factors associated with CRT occurred included VTE history, higher pre-transplant platelet count, and development of severe acute GVHD or active infection. While the type of CVC did not reach statistical significance due to the majority of patients receiving non-tunneled CVC as a standard institutional practice, there was a trend of increased CVC in this group of patients. Future multi-center studies that incorporate different types of CVC will further elucidate this potential association with CRT post-transplant.

Genome-wide cross-trait analysis and Mendelian randomization reveal a shared genetic etiology and causality between COVID-19 and venous thromboembolism

Venous thromboembolism occurs in up to one-third of patients with COVID-19. Venous thromboembolism and COVID-19 may share a common genetic architecture, which has not been clarified. To fill this gap, we leverage summary-level genetic data from the latest COVID‐19 host genetics consortium and UK Biobank and examine the shared genetic etiology and causal relationship between COVID-19 and venous thromboembolism. The cross-trait and co-localization analyses identify 2, 3, and 4 shared loci between venous thromboembolism and severe COVID-19, COVID-19 hospitalization, SARS-CoV-2 infection respectively, which are mapped to ABO, ADAMTS13, FUT2 genes involved in coagulation functions. Enrichment analysis supports shared biological processes between COVID-19 and venous thromboembolism related to coagulation and immunity. Bi-directional Mendelian randomization suggests that venous thromboembolism was associated with higher risk of three COVID-19 traits, and SARS-CoV-2 infection was associated with a higher risk of venous thromboembolism. Our study provides timely evidence for the genetic etiology between COVID-19 and venous thromboembolism (VTE). Our findings contribute to the understanding of COVID-19 and VTE etiology and provide insights into the prevention and comorbidity management of COVID-19.

Thrombosis in Chronic Kidney Disease in Children.

Venous thromboembolism (VTE) in children is a rare condition. An increased incidence has been observed in the last few years due to several factors, such as increased survival in chronic conditions, especially chronic kidney disease (CKD), use of catheters, and increased sensitivity of diagnostic tools. VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE). VTE in children is associated with a two to six times higher mortality risk and a 5-10% prevalence of post-thrombotic syndrome. Overall, 5% of VTE episodes in children are associated with chronic kidney disease. The etiology of VTE in chronic kidney disease covers a wide range of pathologies. Various types of thrombotic complications may occur during long-term use of a chronic dialysis catheter. VTE occurs in 3% of children with nephrotic syndrome (NS). The risks for VTE and arterial thromboembolism (ATE) were particularly high in the first 6 months after the onset of NS. Other causes of VTE are graft rejection due to thrombosis of vascular anastomoses after kidney transplantation (3%) and autoimmune diseases (lupus nephritis, antiphospholipid syndrome). In this state-of-the-art overview, we have reviewed the physiologic and pathologic mechanisms underlying pediatric thrombosis and updated current diagnostic and treatment options, emphasizing personal experience as well.

Integrative analyses of genes about venous thromboembolism: An umbrella review of systematic reviews and meta-analyses.

In recent years, many studies have found possible links between gene polymorphisms and venous thromboembolism (VTE). By identifying genetic risk factors before facing environmental risk factors such as surgical interventions and COVID-19 vaccination, we could rapidly respond to the risk of VTE. The aim of this study was to perform an umbrella review of genetic variants related to VTE. Integrative gene analysis of VTE was performed to identify critical genetic variations. This study conducted an umbrella review of systematic reviews and meta-analyses. All included studies were selected from the PubMed/MEDLINE database. To select eligible studies, the following variables were extracted: first author name; effect size of each study genetic variant; year of publication; the number of studies included in each article; ethnicity, sample size, P values, and heterogeneity estimates. To assess cumulative evidence in genetic epidemiology about effects of gene polymorphisms on VTE, Human Genome Epidemiology Network's Venice criteria were used. Methodological quality assessment was conducted with JBI Critical Appraisal Checklist for Systematic Reviews and Research Syntheses. Genes provided in the present study with genetic variants associated with VTE were FVL (G1691A), Prothrombin (G20210A), MTHFR (C677T, A1298C), PAI-1 (4G/5G), factor VII activating protease (1601G > A), and endothelial protein C receptor (g.6936A_G, c.4600A_G). Among them, variants in FVL, Prothrombin, MTHFR, and PAI-1 showed high significance. Particularly, variants in Prothrombin (G20210A), MTHFR (C677T), and PAI-1 (4G/5G) had more than 2 types of model significance. The present study performed a systematic review of genetic variants associated with VTE. Our results could lead to a more comprehensive understanding of VTE etiology. These results could give a strategy of prediagnosis about evaluating individual risks of VTE who might be exposed to environmental risk factors.

Optimal quality of vitamin K antagonist therapy in Japanese patients with venous thromboembolism

BackgroundVitamin K antagonist (VKA) remains an essential option for venous thromboembolism (VTE), although direct oral anticoagulants have become available. However, there is a paucity of data on the optimal intensity and quality of control for VKA in Japanese. MethodsThe COMMAND VTE Registry is a multicenter registry enrolling consecutive 3027 patients with acute symptomatic VTE among 29 centers in Japan. The current study population consisted of 1938 patients who received VKA with prothrombin time-international normalized ratio (PT-INR) measurement >5 times. The primary outcome measure was a composite of symptomatic VTE recurrence or major bleeding at 1 year. The presumed optimal quality of VKA therapy was defined as the combination of PT-INR range and time in therapeutic range (TTR) with the numerically lowest event rate. ResultsThe group with TTR ≥70 % based on PT-INR range ≥1.5 and <2.0 showed the lowest cumulative incidence rate. The cumulative 1-year incidence and the adjusted risk for the primary outcome measure were significantly lower in the optimal quality group than in the non-optimal quality group (5.2 % vs. 11.7 %, p = 0.001, and HR 0.49, 95%CI 0.28–0.81). Similarly, the cumulative 1-year incidences of a recurrent VTE, major bleeding, and all-cause death were significantly lower in the optimal quality group (recurrent VTE: 2.5 % vs. 6.0 %, p = 0.02; major bleeding: 2.8 % vs. 7.0 %, p = 0.008; and all-cause death: 2.8 % vs. 12.6 %, p < 0.0001). The lower risk of the optimal quality group relative to non-optimal quality group for the clinical outcomes was consistent regardless of the etiology of VTE (active cancer, transient risk factor, and unprovoked). ConclusionsThe current VTE registry showed the optimal intensity of VKA therapy was target PT-INR range ≥1.5 and <2.0, which could support the current Japanese guideline recommendation, and the good quality of control for VKA therapy of TTR ≥70 % was independently associated with better outcomes.

Elevated Risk of Venous Thromboembolism in People Living with HIV.

Human immunodeficiency virus (HIV) has been generally considered as a highly adaptive and rapidly evolving virus. It still constitutes a major public health problem all over the world despite an effective outcome in the prevention and reversal of the development and prognosis by using antiretroviral therapy. The salient question lies in the more frequent emergence of a series of comorbidities along with the prolongation of the life, which deeply affects the survival in such group. Venous thromboembolism (VTE) has been recognized to be the third most common cardiovascular condition within people living with HIV (PWH). In terms of its mechanism of action, the occurrence of VTE is quite multifactorial and complex in HIV. Prior exploration concerning the etiology of VTE in PWH identifies general, disease-specific, and miscellaneous factors for explaining its occurrence and development. VTE has constituted an important role in PWH and may increase its all-cause mortality. Therefore, it is quite necessary to understand VTE from the following aspects of epidemiology, pathophysiology, molecular mechanisms, and therapeutic interventions so as to balance the risks and benefits of anticoagulation and optimize corresponding treatment.

A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant.

Rare variants outside the classical coagulation cascade might cause inherited thrombosis. We aimed to identify the variant(s) causing venous thromboembolism (VTE) in a family with multiple relatives affected with unprovoked VTE and no thrombophilia defects. We identified by whole exome sequencing an extremely rare Arg to Gln variant (Arg89Gln) in the Microtubule Associated Serine/Threonine Kinase 2 (MAST2) gene that segregates with VTE in the family. Free-tissue factor pathway inhibitor (f-TFPI) plasma levels were significantly decreased in affected family members compared to healthy relatives. Conversely, plasminogen activator inhibitor-1 (PAI-1) levels were significantly higher in affected members than in healthy relatives. RNA sequencing analysis of RNA interference experimental data conducted in endothelial cells revealed that, of the 13,387 detected expressed genes, 2,354 have their level of expression modified by MAST2 knockdown, including SERPINE1 coding for PAI-1 and TFPI. In HEK293 cells overexpressing the MAST2 Gln89 variant, TFPI and SERPINE1 promoter activities were respectively lower and higher than in cells overexpressing the MAST2 wild type. This study identifies a novel thrombophilia-causing Arg89Gln variant in the MAST2 gene that is here proposed as a new molecular player in the etiology of VTE by interfering with hemostatic balance of endothelial cells.

Safety and effectiveness of apixaban compared with warfarin among clinically-relevant subgroups of venous thromboembolism patients in the United States Medicare population

BackgroundThe AMPLIFY trial found significantly lower major bleeding (MB) and similar recurrent venous thromboembolism (VTE) risks associated with apixaban vs warfarin among patients with VTE. ObjectivesTo compare MB, clinically-relevant non-major (CRNM) bleeding, and recurrent VTE risks among clinically-relevant subgroups of newly diagnosed elderly patients with VTE prescribed apixaban vs warfarin. MethodsUS Medicare patients prescribed apixaban or warfarin within 30 days post-VTE encounter were identified. Propensity score matching (PSM) was used to control for patient characteristics. Cox models were used to assess MB, CRNM bleeding, and recurrent VTE. Subgroup analyses were conducted for index VTE encounter type, index VTE diagnosis type, index VTE etiology, sex, and frailty. ResultsPost-PSM, 11,363 matched pairs of patients prescribed apixaban or warfarin were identified. Apixaban had lower MB (Hazard Ratio [HR]:0.76; 95% CI:0.64–0.91) and similar recurrent VTE risks (HR:1.04; 95% CI:0.75–1.43) vs warfarin. No significant interactions were observed between treatment and index VTE encounter type, index VTE diagnosis type, or sex for risk of MB, CRNM bleeding, or recurrent VTE. Significant interactions: frail patients prescribed apixaban had a 15% lower, while non-frail patients prescribed apixaban had 32% lower CRNM bleeding risk vs those prescribed warfarin. Patients with provoked VTE prescribed apixaban trended toward a higher, while those with unprovoked VTE trended toward a lower risk of recurrent VTE vs patients prescribed warfarin. ConclusionsApixaban was associated with significantly lower risks of MB and CRNM bleeding, and similar risk of recurrent VTE as compared with warfarin across the overall population and most subgroups.

Risk Factors and Incidence of Venous Thromboembolism after Total Knee Replacement

Patients undergoing total knee arthroplasty can be at risk in developing venous thromboembolism. The etiology of venous thromboembolism after a total knee arthroplasty is multifactorial. The aim of this study is to present the risk factors and the incidence of venous thromboembolism among the 276 patients, who underwent a total of 348 knee arthroplasty treatments in the King Abdulaziz University Hospital. Three hundred (86.2%) patients had undergone unilateral total knee arthroplasty. Only 48 (13.8%) patients had simultaneous bilateral total knee arthroplasty. Their mean length of stays was 11.02 days. venous thromboembolism was present in eight patients (2.3%), either with symptomatic deep vein thrombosis (1.4%) or with pulmonary embolism (1.1%). One hundred twenty-five (35.9%) patients had diabetes, and six of them had developed venous thromboembolism (P-value: 0.020). The mean post-op mobilization (4.63 ± 3.5 days) was higher in cases with venous thromboembolism (P-value: 0.045). Factors, such as the patients’ age, history of venous thromboembolism, gender, history of cerebrovascular, obesity, operation time, and use of preoperative venous thromboembolism prophylaxis, showed no statistical significance with the incidence of venous thromboembolism in them. The result of our study are comparable to those reported in literature. Diabetes mellitus and delayed postoperative mobilization were the significant risk factors to the incidence of venous thromboembolism.

Challenges and Opportunities in the Pharmacological Treatment of Acute Venous Thromboembolism in Children.

Venous thromboembolism (VTE) is an important but historically under-recognized problem in pediatrics, with an incidence concentrated in hospitalized children. A number of specific VTE diseases with discrete triggers have been described, but the most common pediatric trigger is the presence of central venous access devices. VTE diseases, though heterogenous in etiology, are linked by the common therapeutic strategies shared by their management. Historically, the most commonly used drug therapies have been unfractionated heparin, low-molecular-weight heparins, and vitamin K antagonists, based on extrapolation from adult data rather than any specific pediatric trials. Although these widely used drugs appear safe and effective in expert hands, the historical lack of pediatric data is problematic in view of the recognized significant differences between children and adults with regards to hemostatic physiology, VTE etiology, and drug pharmacokinetics. The increasing adult usage of novel VTE pharmacotherapies such as direct oral anticoagulants (DOACs) has led to considerable interest in exploring the pediatric applications of these newer drugs. This review summarizes the advantages and disadvantages of existing VTE pharmacotherapies and outlines emerging novel pediatric VTE therapies, particularly DOACs, within the context of the current pediatric trial landscape.

Clinical risk assessment model to predict venous thromboembolism risk after immobilization for lower-limb trauma

BackgroundPatients with lower-limb trauma requiring immobilization have an increased risk of venous thromboembolism (VTE). While thromboprophylaxis for all patients seems not effective, targeted thromboprophylaxis in high risk patients may be an appropriate alternative. Therefore, we aimed to develop and validate a risk assessment model for VTE risk: the TRiP(cast) score (Thrombosis Risk Prediction following cast immobilization). MethodsIn this prediction model study, for development, data were used from the MEGA study (case-control study into the etiology of VTE) and for validation, data from the POT-CAST trial (randomized trial on the effectiveness of thromboprophylaxis following cast immobilization) were used. Model discrimination was calculated by estimating the Area Under the Curve (AUC). For model calibration, observed and predicted risks were assessed. FindingsThe TRiP(cast) score includes 14 items; one item for trauma severity (or type), one for type of immobilization and 12 items related to patients’ characteristics. Validation analyses showed an AUC of 0.74 (95%CI 0.61–0.87) in the complete dataset (n = 1250) and 0.72 (95%CI 0.60–0.84) in the imputed data set (n = 1435). The calibration plot shows the degree of agreement between the observed and predicted risks (intercept 0.0016 and slope 0.933). Using a cut-off score of 7 points in the POT-CAST trial (incidence 1.6%), the sensitivity, specificity, positive and negative predictive values were 76.1%, 51.2%, 2.5%, and 99.2%, respectively. InterpretationThe TRiP(cast) score provides a helpful tool in daily clinical practice to accurately stratify patients in high versus low-risk categories in order to guide thromboprophylaxis prescribing. To accommodate implementation in clinical practice a mobile phone application has been developed. FundingZonMW VIMP grant:17110200011.

Burden of rare exome sequence variants in PROC gene is associated with venous thromboembolism: a population‐based study

BackgroundRare coding mutations underlying deficiencies of antithrombin and proteins C and S contribute to familial venous thromboembolism (VTE). It is uncertain whether rare variants play a role in the etiology of VTE in the general population. ObjectivesWe conducted a deep whole‐exome sequencing (WES) study to investigate the associations between rare coding variants and the risk of VTE in two population‐based prospective cohorts. Patients/MethodsWhole‐exome sequencing was performed in the Longitudinal Investigation of Thromboembolism Etiology (LITE), which combines the Atherosclerosis Risk in Communities (ARIC) study (316 incident VTE events among 3159 African Americans [AAs] and 458 incident VTEs among 7772 European Americans [EAs]) and the Cardiovascular Healthy Study (CHS; 60 incident VTEs among 1751 EAs). We performed gene‐based tests of rare variants (allele frequency < 1%, exome‐wide significance P < 1.47 × 10−6) separately in each study and ancestry group, and meta‐analyzed the results for the EAs in ARIC and CHS. ResultsIn the meta‐analysis of EAs, we identified one gene, PROC, in which the burden of rare, coding variants was significantly associated with increased risk of VTE (HR = 5.42 [3.11, 9.42] for carriers versus non‐carriers, P = 2.27 × 10−9). In ARIC EAs, carriers of the PROC rare variants had on average 0.75 standard deviation (SD) lower concentrations of plasma protein C and 0.28 SD higher D‐dimer (P < .05) than non‐carriers. Adjustment for low protein C status did not eliminate the association of PROC burden with VTE. In AAs, rare coding PROC variants were not associated with VTE. ConclusionsRare coding variants in PROC contribute to increased VTE risk in EAs in this general population sample.

Abstract P270: Body Size Throughout the Life Course and Risk of Venous Thromboembolism

Introduction: Adult body mass index (BMI) is strongly associated with venous thromboembolism (VTE), however whether earlier-life adiposity or other measures of adult adiposity are associated with VTE risk remains unknown. Hypothesis: Since BMI is a strong risk factor for incident VTE, we hypothesized that early life body size as well as other measures of adult adiposity may also be positively associated with VTE risk. Methods: We evaluated associations of childhood somatotype, BMI at age 18, change in BMI since age 18, and measures of waist and hip circumference with incident VTE among 47,415 women age 40-67 years at baseline from the Nurses’ Health Study (NHS), 47,539 women age 29-48 years from the Nurses’ Health Study II (NHS II), and 32,707 men age 39-76 years from the Health Professionals Follow-Up Study (HPFS) without a prior VTE. We calculated multivariable-adjusted hazard ratios (HR) of VTE using Cox proportional hazards models. Results: Over ≥25 years of follow-up, there were 1,191 incident VTE cases in NHS, 763 cases in NHS II, and 1,350 cases in HPFS. Adult BMI was strongly associated with VTE in all three cohorts (HRs comparing ≥35 kg/m 2 vs. &lt;22.5 kg/m 2 : NHS: 3.03 [95% CI: 2.58, 3.55], NHS II: 3.88 [95% CI: 3.36, 4.48], HPFS: 2.49 [95% CI: 1.83, 3.29]; all P trend&lt; 0.01). Waist circumference, hip circumference, and height were associated with greater VTE risk, even after adjusting for adult BMI (all P trend&lt; 0.01) (Table). Somatotype at ages 5 and 10, BMI at age 18, and change in BMI since age 18 were not significantly associated with VTE risk, after accounting for adult BMI. Conclusions: Adult BMI, waist circumference, hip circumference, and height were independently, positively associated with incident VTE risk. Early life body size was not significantly associated with VTE risk after accounting for adult BMI, indicating that BMI and adiposity are likely more important acutely that cumulatively over time in the etiology of VTE. Clinically, encouraging weight loss in adults

Perioperative bleeding and blood transfusion are major risk factors for venous thromboembolism following bariatric surgery.

Morbidly obese patients are at increased risk for venous thromboembolism (VTE) after bariatric surgery. Perioperative chemoprophylaxis is used routinely with bariatric surgery to decrease the risk of VTE. When bleeding occurs, routine chemoprophylaxis is often withheld due to concerns about inciting another bleeding event. We sought to evaluate the relationship between perioperative bleeding and postoperative VTE in bariatric surgery. The American College of Surgeons-National Surgical Quality Improvement Program (NSQIP) dataset between 2012 and 2014 was queried to identify patients who underwent bariatric surgery. Gastric bypass (n = 28,145), sleeve gastrectomy (n = 30,080), bariatric revision (n = 324), and biliopancreatic diversion procedures (n = 492) were included. Univariate and multivariate regressions were used to determine perioperative factors predictive of postoperative VTE within 30 days in patients who experience a bleeding complication necessitating transfusion. The rate of bleeding necessitating transfusion was 1.3%. Bleeding was significantly more likely to occur in gastric bypass compared to sleeve gastrectomy (1.6 vs. 1.0%) (p < 0.0001). For all surgeries, increased age, length of stay, operative time, and comorbidities including hypertension, dyspnea with moderate exertion, partially dependent functional status, bleeding disorder, transfusion prior to surgery, ASA class III/IV, and metabolic syndrome increased the perioperative bleeding risk (p < 0.05). Multivariate analysis revealed that the rate of VTE was significantly higher after blood transfusion [Odds Ratio (OR) = 4.7; 95% CI 2.9-7.9; p < 0.0001). Predictive risk factors for VTE after transfusion included previous bleeding disorder, ASA class III or IV, and COPD (p < 0.05). Bariatric surgery patients who receive postoperative blood transfusion are at a significantly increased risk for VTE. The etiology of VTE in those who are transfused is likely multifactorial and possibly related to withholding chemoprophylaxis and the potential of a hypercoagulable state induced by the transfusion. In those who bleed, consideration should be given to reinitiating chemoprophylaxis when safe, extending treatment after discharge, and screening ultrasound.

Time-dependent risk and predictors of venous thromboembolism in breast cancer patients: A population-based cohort study.

Venous thromboembolism (VTE) is a serious complication of cancer and its treatment. The current study assessed the risk and clinical predictors of VTE in breast cancer patients by time since diagnosis. This Swedish population-based study included 8338 breast cancer patients diagnosed from 2001 to 2008 in the Stockholm-Gotland region with complete follow-up until 2012. Their incidence of VTE was compared with the incidence among 39,013 age-matched reference individuals from the general population. Cox and flexible parametric models were used to examine associations with patient, tumor, and treatment characteristics, accounting for time-dependent effects. Over a median follow-up of 7.2 years, 426 breast cancer patients experienced a VTE event (cumulative incidence, 5.1%). The VTE incidence was 3-fold increased (hazard ratio [HR], 3.28; 95% confidence interval [CI], 2.87-3.74) in comparison with the incidence in the general population and was highest 6 months after diagnosis (HR, 8.62; 95% CI, 6.56-11.33) with a sustained increase in risk thereafter (HR at 5 years, 2.19; 95% CI, 1.80-2.67). Independent predictors of VTE included the following: older age, being overweight, preexisting VTE, comorbid disease, tumor size > 40 mm, progesterone receptor (PR)-negative status, more than 4 affected lymph nodes, and receipt of chemo- and endocrine therapy. The impact of chemotherapy was limited to early-onset VTE, whereas comorbid disease and PR-negative status were more strongly associated with late-onset events. This study confirms the long-term risk of VTE in breast cancer patients and identifies a comprehensive set of clinical risk predictors. Temporal associations with patient, tumor, and treatment characteristics provide insight into the time-dependent etiology of VTE. Cancer 2017;123:468-475. © 2016 American Cancer Society.

Cognitive ability in Swedish conscripts and future risk of venous thromboembolism: A co-relative prospective national study

ObjectiveCognitive ability measured via an IQ-test (intelligence quotient) has been associated with cardiovascular (CVD) incidence. Whether cognitive ability is associated with risk of venous thromboembolism (VTE) is unknown. The present nationwide co-relative study aims to determine whether cognitive ability in male conscripts is a predictor of VTE. MethodsA Swedish cohort of male conscripts (n=940,964) born in 1954–1970 with no history of previous VTE were followed from enlistment (1972–1990) until 2010. Data on cognitive ability, using an IQ-test at conscription, were linked with national hospital register data to calculate future risk of VTE requiring in-patient care. Using the Swedish Multi-Generation Register, we identified all full-siblings, half-siblings and first-cousin pair discordant for IQ. This co-relative design allows for adjustment for unmeasured shared genetic or environmental factors. ResultsA total of 5110 (0.54%) males were affected by VTE. IQ was associated with risk for VTE (hazard ratio=HR 0.87 95% confidence interval 0.84–0.89 per standard deviation [SD] increment). The association was highly time dependent with attenuation of effect over time and significant interaction between time and IQ. IQ was also associated with VTE in first-cousin pairs (HR=0.74, 0.69–0.79) but not when examining discordant half-sibling pairs (HR=0.94, 0.82–1.08), and only weakly in full-sibling pairs (HR=0.91, 0.84–0.98). ConclusionsThe present study suggests that familial-shared environmental factors linked to cognitive ability might be involved in the etiology of VTE. However, it is unlikely that IQ by itself causes VTE.

Venous Thrombosis Risk after Cast Immobilization of the Lower Extremity: Derivation and Validation of a Clinical Prediction Score, L-TRiP(cast), in Three Population-Based Case–Control Studies

BackgroundGuidelines and clinical practice vary considerably with respect to thrombosis prophylaxis during plaster cast immobilization of the lower extremity. Identifying patients at high risk for the development of venous thromboembolism (VTE) would provide a basis for considering individual thromboprophylaxis use and planning treatment studies.The aims of this study were (1) to investigate the predictive value of genetic and environmental risk factors, levels of coagulation factors, and other biomarkers for the occurrence of VTE after cast immobilization of the lower extremity and (2) to develop a clinical prediction tool for the prediction of VTE in plaster cast patients.Methods and FindingsWe used data from a large population-based case–control study (MEGA study, 4,446 cases with VTE, 6,118 controls without) designed to identify risk factors for a first VTE. Cases were recruited from six anticoagulation clinics in the Netherlands between 1999 and 2004; controls were their partners or individuals identified via random digit dialing. Identification of predictor variables to be included in the model was based on reported associations in the literature or on a relative risk (odds ratio) > 1.2 and p ≤ 0.25 in the univariate analysis of all participants. Using multivariate logistic regression, a full prediction model was created. In addition to the full model (all variables), a restricted model (minimum number of predictors with a maximum predictive value) and a clinical model (environmental risk factors only, no blood draw or assays required) were created. To determine the discriminatory power in patients with cast immobilization (n = 230), the area under the curve (AUC) was calculated by means of a receiver operating characteristic. Validation was performed in two other case–control studies of the etiology of VTE: (1) the THE-VTE study, a two-center, population-based case–control study (conducted in Leiden, the Netherlands, and Cambridge, United Kingdom) with 784 cases and 523 controls included between March 2003 and December 2008 and (2) the Milan study, a population-based case–control study with 2,117 cases and 2,088 controls selected between December 1993 and December 2010 at the Thrombosis Center, Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico, Milan, Italy.The full model consisted of 32 predictors, including three genetic factors and six biomarkers. For this model, an AUC of 0.85 (95% CI 0.77–0.92) was found in individuals with plaster cast immobilization of the lower extremity. The AUC for the restricted model (containing 11 predictors, including two genetic factors and one biomarker) was 0.84 (95% CI 0.77–0.92). The clinical model (consisting of 14 environmental predictors) resulted in an AUC of 0.77 (95% CI 0.66–0.87). The clinical model was converted into a risk score, the L-TRiP(cast) score (Leiden–Thrombosis Risk Prediction for patients with cast immobilization score), which showed an AUC of 0.76 (95% CI 0.66–0.86). Validation in the THE-VTE study data resulted in an AUC of 0.77 (95% CI 0.58–0.96) for the L-TRiP(cast) score. Validation in the Milan study resulted in an AUC of 0.93 (95% CI 0.86–1.00) for the full model, an AUC of 0.92 (95% CI 0.76–0.87) for the restricted model, and an AUC of 0.96 (95% CI 0.92–0.99) for the clinical model. The L-TRiP(cast) score resulted in an AUC of 0.95 (95% CI 0.91–0.99).Major limitations of this study were that information on thromboprophylaxis was not available for patients who had plaster cast immobilization of the lower extremity and that blood was drawn 3 mo after the thrombotic event.ConclusionsThese results show that information on environmental risk factors, coagulation factors, and genetic determinants in patients with plaster casts leads to high accuracy in the prediction of VTE risk. In daily practice, the clinical model may be the preferred model as its factors are most easy to determine, while the model still has good predictive performance. These results may provide guidance for thromboprophylaxis and form the basis for a management study.

Meta-analysis of 65,734 Individuals Identifies TSPAN15 and SLC44A2 as Two Susceptibility Loci for Venous Thromboembolism

Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5× 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67× 10(-16)) and 1.21 (p = 2.75× 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.

Treatment of Venous Thromboembolism

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common, potentially lethal condition with acute morbidity. To review the etiology of VTE and the 3 phases of VTE treatment: acute (first 5-10 days), long-term (from end of acute treatment to 3-6 months), and extended (beyond 3-6 months). Cochrane reviews, meta-analyses, and randomized controlled trials, as well as other clinical trials for topics not covered by the former, were reviewed. Literature searches using broad terms were used to find meta-analyses published in the last 15 years. The ninth edition of the American College of Chest Physicians Antithrombotic Therapy Guidelines was used to supplement the literature search. Guidelines from specialty organizations were consulted when relevant. The Canadian Agency for Drugs and Technologies in Health was searched for relevant cost-effectiveness studies. We also searched our own literature database of 8386 articles for relevant research. Low-molecular-weight heparin (LMWH) along with with vitamin K antagonists and the benefits and proven safety of ambulation have allowed for outpatient management of most cases of DVT in the acute phase. Development of new oral anticoagulants further simplifies acute-phase treatment and 2 oral agents can be used as monotherapy, avoiding the need for LMWH. Patients with PE can also be treated in the acute phase as outpatients, a decision dependent on prognosis and severity of PE. Thrombolysis is best reserved for severe VTE; inferior vena cava filters, ideally the retrievable variety, should be used when anticoagulation is contraindicated. In general, DVT and PE patients require 3 months of treatment with anticoagulants, with options including LMWH, vitamin K antagonists, or direct factor Xa or direct factor IIa inhibitors. After this time, decisions for further treatment are based on balancing the risk of VTE recurrence, determined by etiology of the VTE (transient risk factors, unprovoked or malignancy associated), against the risk of major hemorrhage from treatment. Better prediction tools for major hemorrhage are needed. Experience with new oral anticoagulants as acute, long-term, and extended therapy options is limited as yet, but as a class they appear to be safe and effective for all phases of treatment. The mainstay of VTE treatment is anticoagulation, while interventions such as thrombolysis and inferior vena cava filters are reserved for limited circumstances. Multiple therapeutic modes and options exist for VTE treatment with small but nonetheless important differential effects to consider. Anticoagulants will probably always increase bleeding risk, necessitating tailored treatment strategies that must incorporate etiology, risk, benefit, cost, and patient preference. Although great progress has been made, further study to understand individual patient risks is needed to make ideal treatment decisions.