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The actual incidence of neurologic dysfunction resulting from hemorrhagic complications associated with neuraxial blockade is unknown. Although the incidence cited in the literature is estimated to be less than 1 in 150,000 epidural and less than 1 in 220,000 spinal anesthetics, recent epidemiologic surveys suggest that the frequency is increasing and may be as high as 1 in 3000 in some patient populations.Overall, the risk of clinically significant bleeding increase with age,associated abnormalities of the spinal cord or vertebral column, the presence of an underlying coagulopathy, difficulty during needle placement,and an indwelling neuraxial catheter during sustained anticoagulation( particularly with standard heparin or low-molecular weight heparin). The need for prompt diagnosis and intervention to optimize neurologic outcome is also consistently reported. In response to these patient safety issues, the American Society of Regional Anesthesia and Pain Medicine (ASRA) convened its Third Consensus Conference on Regional Anesthesia and Anticoagulation. Practice guidelines or recommendations summarize evidence-based reviews. However, the rarity of spinal hematoma defies a prospective randomized study, and there is no current laboratory model. As a result,the ASRA consensus statements represent the collective experience of recognized experts in the field of neuraxial anesthesia and anticoagulation. These are based on case reports, clinical series, pharmacology,hematology, and risk factors for surgical bleeding. An understanding of the complexity of this issue is essential to patient management. [ABSTRACT FROM AUTHOR]

Background: VTE is a common cause of preventable death in surgical patients.Methods: We developed recommendations for thromboprophylaxis in nonorthopedic surgical patients by using systematic methods as described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.Results: We describe several alternatives for stratifying the risk of VTE in general and abdominal-pelvic surgical patients. When the risk for VTE is very low (< 0.5%), we recommend that no specific pharmacologic (Grade 1B) or mechanical (Grade 2C) prophylaxis be used other than early ambulation. For patients at low risk for VTE (∼1.5%), we suggest mechanical prophylaxis, preferably with intermittent pneumatic compression (IPC), over no prophylaxis (Grade 2C). For patients at moderate risk for VTE (∼3%) who are not at high risk for major bleeding complications, we suggest low-molecular-weight heparin (LMWH) (Grade 2B), low-dose unfractionated heparin (Grade 2B), or mechanical prophylaxis with IPC (Grade 2C) over no prophylaxis. For patients at high risk for VTE (∼6%) who are not at high risk for major bleeding complications, we recommend pharmacologic prophylaxis with LMWH (Grade 1B) or low-dose unfractionated heparin (Grade 1B) over no prophylaxis. In these patients, we suggest adding mechanical prophylaxis with elastic stockings or IPC to pharmacologic prophylaxis (Grade 2C). For patients at high risk for VTE undergoing abdominal or pelvic surgery for cancer, we recommend extended-duration, postoperative, pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis (Grade 1B). For patients at moderate to high risk for VTE who are at high risk for major bleeding complications or those in whom the consequences of bleeding are believed to be particularly severe, we suggest use of mechanical prophylaxis, preferably with IPC, over no prophylaxis until the risk of bleeding diminishes and pharmacologic prophylaxis may be initiated (Grade 2C). For patients in all risk groups, we suggest that an inferior vena cava filter not be used for primary VTE prevention (Grade 2C) and that surveillance with venous compression ultrasonography should not be performed (Grade 2C). We developed similar recommendations for other nonorthopedic surgical populations.Conclusions: Optimal thromboprophylaxis in nonorthopedic surgical patients will consider the risks of VTE and bleeding complications as well as the values and preferences of individual patients. [ABSTRACT FROM AUTHOR]

Background: Although exogenous estrogenic therapies increase the risk of thrombosis, the effects of estrogen on formed elements of blood are uncertain.Objective: This article examines the genomic and nongenomic actions of estrogen on platelet phenotype that may contribute to increased thrombotic risk.Methods: To determine aggregation, secretion, protein expression, and thrombin generation, platelets were collected from experimental animals of varying hormonal status and from women enrolled in the Kronos Early Estrogen Prevention Study.Results: Estrogen receptor beta predominates in circulating platelets. Estrogenic treatment in ovariectomized animals decreased platelet aggregation and adenosine triphosphate (ATP) secretion. However, acute exposure to 17beta-estradiol did not reverse decreases in platelet ATP secretion invoked by lipopolysaccharide. Thrombin generation was positively correlated to the number of circulating microvesicles expressing phosphatidylserine.Conclusion: Assessing the effect of estrogen treatments on blood platelets may lead to new ways of identifying women at risk for adverse thrombotic events with such therapies. [ABSTRACT FROM AUTHOR]

This article discusses the prevention of venous thromboembolism (VTE) and is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh risks, burden, and costs. Grade 2 suggestions imply that individual patient values may lead to different choices (for a full discussion of the grading, see the "Grades of Recommendation" chapter by Guyatt et al). Among the key recommendations in this chapter are the following: we recommend that every hospital develop a formal strategy that addresses the prevention of VTE (Grade 1A). We recommend against the use of aspirin alone as thromboprophylaxis for any patient group (Grade 1A), and we recommend that mechanical methods of thromboprophylaxis be used primarily for patients at high bleeding risk (Grade 1A) or possibly as an adjunct to anticoagulant thromboprophylaxis (Grade 2A). For patients undergoing major general surgery, we recommend thromboprophylaxis with a low-molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH), or fondaparinux (each Grade 1A). We recommend routine thromboprophylaxis for all patients undergoing major gynecologic surgery or major, open urologic procedures (Grade 1A for both groups), with LMWH, LDUH, fondaparinux, or intermittent pneumatic compression (IPC). For patients undergoing elective hip or knee arthroplasty, we recommend one of the following three anticoagulant agents: LMWH, fondaparinux, or a vitamin K antagonist (VKA); international normalized ratio (INR) target, 2.5; range, 2.0 to 3.0 (each Grade 1A). For patients undergoing hip fracture surgery (HFS), we recommend the routine use of fondaparinux (Grade 1A), LMWH (Grade 1B), a VKA (target INR, 2.5; range, 2.0 to 3.0) [Grade 1B], or LDUH (Grade 1B). We recommend that patients undergoing hip or knee arthroplasty or HFS receive thromboprophylaxis for a minimum of 10 days (Grade 1A); for hip arthroplasty and HFS, we recommend continuing thromboprophylaxis > 10 days and up to 35 days (Grade 1A). We recommend that all major trauma and all spinal cord injury (SCI) patients receive thromboprophylaxis (Grade 1A). In patients admitted to hospital with an acute medical illness, we recommend thromboprophylaxis with LMWH, LDUH, or fondaparinux (each Grade 1A). We recommend that, on admission to the ICU, all patients be assessed for their risk of VTE, and that most receive thromboprophylaxis (Grade 1A). [ABSTRACT FROM AUTHOR]

This article discusses the prevention of venous thromboembolism (VTE) and is part of the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this chapter are the following. We recommend against the use of aspirin alone as thromboprophylaxis for any patient group (Grade 1A). For moderate-risk general surgery patients, we recommend prophylaxis with low-dose unfractionated heparin (LDUH) (5,000 U bid) or low-molecular-weight heparin (LMWH) [< or = 3,400 U once daily] (both Grade 1A). For higher risk general surgery patients, we recommend thromboprophylaxis with LDUH (5,000 U tid) or LMWH (> 3,400 U daily) [both Grade 1A]. For high-risk general surgery patients with multiple risk factors, we recommend combining pharmacologic methods (LDUH three times daily or LMWH, > 3,400 U daily) with the use of graduated compression stockings and/or intermittent pneumatic compression devices (Grade 1C+). We recommend that thromboprophylaxis be used in all patients undergoing major gynecologic surgery (Grade 1A) or major, open urologic procedures, and we recommend prophylaxis with LDUH two times or three times daily (Grade 1A). For patients undergoing elective total hip or knee arthroplasty, we recommend one of the following three anticoagulant agents: LMWH, fondaparinux, or adjusted-dose vitamin K antagonist (VKA) [international normalized ratio (INR) target, 2.5; range, 2.0 to 3.0] (all Grade 1A). For patients undergoing hip fracture surgery (HFS), we recommend the routine use of fondaparinux (Grade 1A), LMWH (Grade 1C+), VKA (target INR, 2.5; range, 2.0 to 3.0) [Grade 2B], or LDUH (Grade 1B). We recommend that patients undergoing hip or knee arthroplasty, or HFS receive thromboprophylaxis for at least 10 days (Grade 1A). We recommend that all trauma patients with at least one risk factor for VTE receive thromboprophylaxis (Grade 1A). In acutely ill medical patients who have been admitted to the hospital with congestive heart failure or severe respiratory disease, or who are confined to bed and have one or more additional risk factors, we recommend prophylaxis with LDUH (Grade 1A) or LMWH (Grade 1A). We recommend, on admission to the intensive care unit, all patients be assessed for their risk of VTE. Accordingly, most patients should receive thromboprophylaxis (Grade 1A). [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is a common and potentially lethal disease that recurs frequently and is associated with long-term impairment and suffering. Despite a great deal of effort, the incidence of VTE has not changed substantially in the last 20 years. Independent risk factors include hospitalization (either for surgery or for acute medical illness), trauma, malignant neoplasm, central venous catheters or transvenous pacemakers, superficial vein thrombosis, and extremity paresis. Of these, hospitalization accounts for almost 60% of all VTE occurring in the community. Thus, universal effective prophylaxis of hospitalized patients would significantly reduce the incidence of VTE. Parenteral direct thrombin inhibitors are safe and effective for both prevention and treatment of acute VTE, and do not require laboratory monitoring or dose adjustment. Oral direct thrombin inhibitors may also be safe and effective, and offer enhanced convenience without diet or drug-drug interactions. [ABSTRACT FROM AUTHOR]

Objectives: We sought to determine the association between patent foramen ovale (PFO), atrial septal aneurysm (ASA), and stroke prospectively in a unselected population sample. Background: The disputed relationship between PFO and stroke reflects methodologic weaknesses in studies using invalid controls, unblinded transesophageal echocardiography examinations, and data that are unadjusted for age or comorbidity. Methods: The use of transesophageal echocardiography to identify PFO was performed by a single echocardiographer using standardized definitions in 585 randomly sampled, Olmsted County (Minnesota) subjects age 45 years or older participating in the Stroke Prevention: Assessment of Risk in a Community (SPARC) study. Results: A PFO was identified in 140 (24.3%) subjects and ASA in 11 (1.9%) subjects. Of the 140 subjects with PFO, 6 (4.3%) had an ASA; of the 437 subjects without PFO, 5 had an ASA (1.1%, two-sided Fisher exact test, p = 0.028). During a median follow-up of 5.1 years, cerebrovascular events (cerebrovascular disease-related death, ischemic stroke, transient ischemic attack) occurred in 41 subjects. After adjustment for age and comorbidity, PFO was not a significant independent predictor of stroke (hazard ratio 1.46, 95% confidence interval 0.74 to 2.88, p = 0.28). The risk of a cerebrovascular event among subjects with ASA was nearly four times higher than that in those without ASA (hazard ratio 3.72, 95% confidence interval 0.88 to 15.71, p = 0.074). Conclusions: These prospective population-based data suggest that, after correction for age and comorbidity, PFO is not an independent risk factor for future cerebrovascular events in the general population. A larger study is required to test the putative stroke risk associated with ASA. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To estimate the 3-month cumulative incidence of thromboembolism (TE), bleeding, and death among consecutive patients with nonvalvular atrial fibrillation (AF) who were receiving long-term anticoagulation therapy and were referred to the Thrombophilia Center at Mayo Clinic for periprocedural anticoagulation management. PATIENTS AND METHODS: In a prospective cohort study of consecutive patients receiving long-term anticoagulation therapy who were referred to the Thrombophilia Center for periprocedural anticoagulation management over the 7-year period, January 1, 1997, to December 31, 2003, 345 patients with nonvalvular AF were eligible for inclusion. Warfarin was stopped 4 to 5 days before and was restarted after surgery as soon as hemostasis was assured. The decision to provide bridging therapy with heparin was individualized and based on the estimated risks of TE and bleeding. RESULTS: The 345 patients with AF (mean +/- SD age, 74+/-9 years; 33% women) underwent 386 procedures. Warfarin administration was not interrupted for 44 procedures. Periprocedural heparin was provided for 204 procedures. Patients receiving heparin were more likely to have prior TE (43% vs 24%; P<.001) and a higher CHADS2 (congestive heart failure, hypertension, age, diabetes, stroke) score (2.2 vs 1.9; P=.06). Four patients had 6 episodes of TE (3 strokes and 3 acute coronary episodes; TE rate, 1.1%; 95% confidence interval, 0.0%-2.1%). Nine patients had 10 major bleeding events (major bleeding rate, 2.7%; 95% confidence interval, 1.0%-4.4%). There were no deaths. Neither bleeding nor TE rates differed by anticoagulant management strategy. CONCLUSION: The 3-month cumulative incidence of TE and bleeding among patients with AF in whom anticoagulation was temporarily interrupted for an invasive procedure was low and was not significantly influenced by bridging therapy. [ABSTRACT FROM AUTHOR]

Objective: To determine risk factors for venous thromboembolism (VTE) among nursing home (NH) residents.Participants and Methods: This population-based historical cohort study used Minnesota Case Mix Review Program (MCMRP) Public Research Files to identify all unique Olmsted County, Minnesota, residents in any local NH from January 1, 1988, through December 31, 1994. Cases were defined as residents with a VTE diagnosis at any NH assessment. For each case, we identified 2 age- and sex-matched controls, defined as NH residents who did not have VTE but were assessed in the year of the case's earliest VTE diagnosis (ie, index assessment). Cases and controls were compared for preindex assessment characteristics. Accuracy of MCMRP VTE ascertainment was explored by comparing MCMRP cases with members of the Rochester Epidemiology Project incident cohort who were objectively diagnosed with VTE from January 1, 1988, through December 31, 1994, while residing in an Olmsted County NH.Results: At the preindex assessment, cases were more likely than controls to have returned from hospital; to require assistance with grooming, toileting, transferring, bed positioning, or wheelchair use; or to need physical therapy, rehabilitation, clinical monitoring, or wound care and were less likely to have neurologic disease. There were 53 MCMRP VTE cases vs 161 Rochester Epidemiology Project NH VTE cases; the proportion with pulmonary embolism was 21% vs 62%; 1-year mortality was 24% vs 55%.Conclusion: Administrative data from NHs reveal important VTE risk factors not routinely documented in hospital or ambulatory records. However, ascertainment of VTE from NH administrative data appears biased toward surviving cases, highlighting concerns about using such data to assess provider quality and pointing to the need for studies that track individuals through multiple data sources across institutional settings. [ABSTRACT FROM AUTHOR]

Objective: To determine the sensitivity and specificity of a quantitative plasma fibrin D-dimer latex immunoassay (LIA) for the diagnosis of acute pulmonary embolism. Subjects and Methods: Study subjects were Mayo Clinic Rochester inpatients and outpatients with suspected acute pulmonary embolism; all had undergone quantitative D-dimer LIA testing and multidetector-row computed tomographic (CT) angiography between August 3, 2001, and November 10, 2003. Multidetector-row CT angiography was the diagnostic reference standard. Results: Of 1355 CT studies, 208 (15%) were positive for acute pulmonary embolism. Median D-dimer levels were significantly higher for patients with acute pulmonary embolism (1425 ng/mL) than for patients without (500 ng/mL) (P<.001). The highest specificity that optimizes sensitivity for acute pulmonary embolism was achieved by using a discriminant value of 300 ng/mL, which yielded a sensitivity of 0.94 (95% confidence interval [CI], 0.89-0.97), a specificity of 0.27 (95% CI, 0.25-0.30), and a negative predictive value of 0.96 (95% CI, 0.93-0.98). Conclusion: The quantitative D-dimer LIA with a discriminant value of 300 ng/mL had high sensitivity and high negative predictive value but low specificity for the diagnosis of acute pulmonary embolism. On the basis of these results, we believe that a negative quantitative D-dimer LIA result and a low pretest probability of thromboembolism together are sufficient to exclude acute pulmonary embolism. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To assess the performance of 4 clotting assays for lupus anticoagulant (LA) detection, to determine the prevalence of LA and anticardiolipin antibodies (aCL), and to correlate LA and aCL prevalence with systemic disease and thrombosis. PATIENTS AND METHODS: We studied 664 consecutive patients at the Mayo Clinic in Rochester, Minn, who were referred for laboratory testing because of a clinical suspicion of LA or thrombophilia between June 25, 1990, and July 1, 1991. RESULTS: Of 664 patients tested for LA, 584 also were tested for aCL. Of patients tested for both LA and aCL, 137 (235%) had positive results for one or both tests (13 [95%], LA-positive only; 76 [555%], aCL-positive only; and 48 [35.0%], positive for both). The dilute Russell viper venom time (DRVVT) was the most frequently positive LA assay (74% of the 61 patients with positive results for LA). Twenty-two patients (36.1% of the 61) had positive results for all 4 LA assays, whereas 21 (34.4% of the 61) had positive results for only 1 LA assay: activated partial thromboplastin time (3 patients [4.9%]), plasma clot time (5 patients [8.2%]), kaolin clot time (5 patients [8.2%]), or DRVVT (8 patients [13.1%]). Thromboembolism prevalence was not definitely associated with positive test results (LA only, aCL only, or LA plus aCL), nor was it strongly associated with aCL isotype or titer. Furthermore, thromboembolism prevalence was not increased when all LA assays were positive, although a history of deep venous thrombosis or pulmonary embolism was nonsignificantly associated with positive results for all 4 LA tests. The likelihood of having both LA- and aCL-positive test results was higher among patients with systemic lupus erythematosus (26 [19.0%] of 137 patients with positive results for one or both tests), but they had no more thrombotic events or fetal loss than other patients in our study group. CONCLUSIONS: The DRVVT identified more patients with LA than the other LA tests, but more than 1 LA test was required to identify all patients with LA. Positive results were much more common for aCL than for LA. No single LA test or anticardiolipin isotype correlated with thrombosis or systemic disease in this population. [ABSTRACT FROM AUTHOR]

Objective: To determine the sensitivity and specificity of the semiquantitative latex agglutination plasma fibrin D-dimer assay for the diagnosis of acute pulmonary embolism by using computed tomographic (CT) angiography as the diagnostic reference standard. Patients and Methods: From January 1, 1998, to June 26, 2000, patients who had both semiquantitative latex agglutination plasma fibrin D-dimer testing and CT angiography for suspected acute pulmonary embolism were selected for the study. A D-dimer value greater than 250 ng/mL was considered positive for thromboembolic disease. Diagnosis of acute pulmonary embolism was based solely on the interpretation of the CT angiogram. The D-dimer assay results were then compared with the CT angiographic diagnoses. Results: Of 946 CT studies, 172 (18%) were positive for acute pulmonary embolism. The D-dimer assay was positive for 612 (65%) of the 946 patients. For acute pulmonary embolism, the D-dimer assay had a sensitivity of 0.83 (95% confidence interval [CI], 0.76-0.88), a specificity of 039 (95% CI, 036-0.43), a negative likelihood ratio of 0.44 (95 % CI, 032-0.62), and a negative predictive value of 0.91 (95% CI, 0.87-0.94). Conclusions: The semiquantitative latex agglutination plasma fibrin D-dimer assay had moderate sensitivity and low specificity for the diagnosis of acute pulmonary embolism. When used alone, the results of this test were insufficient to exclude this serious and potentially fatal disorder. Approximately two thirds of our patients had positive D-dimer assays and required further evaluation to exclude acute pulmonary embolism. [ABSTRACT FROM AUTHOR]

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown 1 . The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer 2-4 and coronary heart disease 5 -this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP) 6 . Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

Platelet transmission electron microscopy (PTEM) is considered the gold standard test for assessing distinct ultrastructural abnormalities in inherited platelet disorders (IPDs). Nevertheless, PTEM remains mainly a research tool due to the lack of standardized procedures, a validated dense granule (DG) count reference range, and standardized image interpretation criteria. The aim of this study was to standardize and validate PTEM as a clinical laboratory test. Based on previously established methods, we optimized and standardized preanalytical, analytical, and postanalytical procedures for both whole mount (WM) and thin section (TS) PTEM. Mean number of DG/platelet (plt), percentage of plts without DG, platelet count (PC), mean platelet volume (MPV), immature platelet fraction (IPF), and plt light transmission aggregometry analyses were measured on blood samples from 113 healthy donors. Quantile regression was used to estimate the reference range for DG/plt, and linear regression was used to assess the association of DG/plt with other plt measurements. All PTEM procedures were standardized using commercially available materials and reagents. DG interpretation criteria were established based on previous publications and expert consensus, and resulted in improved operator agreement. Mean DG/plt was stable for 2 days after blood sample collection. The median within patient coefficient of variation for mean DG/plt was 22.2%; the mean DG/plt reference range (mid-95th %) was 1.2-4.0. Mean DG/plt was associated with IPF (p = .01, R 2  = 0.06) but not age, sex, PC, MPV, or plt maximum aggregation or primary slope of aggregation (p > .17, R 2  < 0.02). Baseline ultrastructural features were established for TS-PTEM. PTEM was validated using samples from patients with previously established diagnoses of IPDs. Standardization and validation of PTEM procedures and interpretation, and establishment of the normal mean DG/plt reference range and PTEM baseline ultrastructural features, will facilitate implementation of PTEM as a valid clinical laboratory test for evaluating ultrastructural abnormalities in IPDs.

Nursing home (NH) residency is an independent risk factor for venous thromboembolism (VTE), but the VTE burden within the NH population is uncertain. This study estimates VTE incidence and VTE-associated mortality among NH residents. We identified all NH residents in any NH in Olmsted County, Minnesota, United States, 1 October 1998 to 31 December 2005 and all first lifetime VTE among county residents to estimate VTE incidence while resident of local NHs (NHVTE), using Centers for Medicare and Medicaid Services Minimum Data Set and Rochester Epidemiology Project resources. We tested associations between NHVTE and age, sex and time since each NH admission using Poisson modelling. Additionally, we tested incident NHVTE as a potential predictor of survival using Cox proportional hazards, adjusting for age, sex and NH residency. Between 1 October 1998 and 31 December 2005, 3,465 Olmsted County residents with ≥1 admission to a local NH, contributed 4,762 NH stays. Of the 3,465 NH residents, 111 experienced incident NHVTE (2.3% of all eligible stays), for an overall rate of 3,653/100,000 NH person-years (NH-PY). VTE incidence was inversely associated with time since each NH admission, and was highest in the first 7 days after each NH admission (18,764/100,000 NH-PY). The adjusted hazard of death for incident NHVTE was 1.90 (95% confidence interval [CI]: 1.38-2.62). In conclusion, VTE incidence among NH residents was nearly 30-fold higher than published incidence rates for the general Olmsted County population. VTE incidence was highest within 7 days after NH admission, and NHVTE was associated with significantly reduced survival. These data can inform future research and construction of clinical trials regarding short-term prophylaxis., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

The co-author name Immaculata DeVivo was incorrectly published. The correct name is given below.

Background: The independent association of recent infection with venous thromboembolism is uncertain. The study aims were to test both overall infection (site unspecified) and specific infection sites as potential risk factors for deep vein thrombosis and pulmonary embolism adjusting for other known venous thromboembolism factors., Methods: By using Rochester Epidemiology Project resources, we identified all Olmsted County, Minnesota, residents with objectively diagnosed incident deep vein thrombosis or pulmonary embolism over the 13-year period 1988 to 2000 (cases; n = 1303) and 1 to 2 residents without venous thromboembolism matched to each case on age, sex, and incident venous thromboembolism date (controls; n = 1494). Using conditional logistic regression, we tested recent infection and infection site(s) for an association with venous thromboembolism, adjusting for body mass index, smoking, current/recent hospitalization with/without surgery, nursing home confinement, active cancer, trauma/fracture, leg paresis, prior superficial vein thrombosis, transvenous catheter/pacemaker, ischemic heart disease, congestive heart failure, chronic lung or renal disease, serious liver disease, asthma, diabetes mellitus, hormone therapy, and pregnancy/postpartum., Results: A total of 513 cases (39.4%) and 189 controls (12.7%) had an infection in the previous 92 days (odds ratio, 4.5; 95% confidence interval, 3.6-5.5; P < .0001). In a multivariable analysis adjusting for common venous thromboembolism risk factors, pneumonia and symptomatic urinary tract, oral, intra-abdominal, and systemic bloodstream infections were associated with significantly increased odds of venous thromboembolism., Conclusions: Infection as a whole and specific infection sites in particular are independent risk factors for venous thromboembolism and should be considered as potential indications for venous thromboembolism prophylaxis., (Copyright © 2018. Published by Elsevier Inc.)

Coronary embolism is the underlying cause of 3% of acute coronary syndromes but is often not considered in the differential of acute coronary syndromes. It should be suspected in the case of high thrombus burden despite a relatively normal underlying vessel or recurrent coronary thrombus. Coronary embolism may be direct (from the aortic valve or left atrial appendage), paroxysmal (from the venous circulation through a patent foramen ovale), or iatrogenic (following cardiac intervention). Investigations include transesophageal echocardiography to assess the left atrial appendage and atrial septum and continuous electrocardiographic monitoring to assess for paroxysmal atrial fibrillation. The authors review the historic and contemporary published data about this important cause of acute coronary syndromes. The authors propose an investigation and management strategy for work-up and anticoagulation strategy for patients with suspected coronary embolism., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Women with inherited antithrombin (AT) deficiency are at high risk for venous thromboembolism (VTE), especially during times of estrogen exposure, but little is known about patient-oriented reproductive decision-making in this population., Materials and Methods: Provider-administered survey of women with AT deficiency. Participants were asked to discuss their diagnosis of AT deficiency and questioned about (1) contraception, (2) pregnancies, and (3) menorrhagia, and the impact of their AT deficiency on each reproductive health experience., Results: Of 31 women with inherited AT deficiency, 18 (58%) were surveyed, 8 (26%) were unreachable, and 5 (16%) were deceased. Twelve (67%) had a VTE, including two which occurred during pregnancy and five during oral contraceptive (OCP) use. Women reported using OCPs, intrauterine device (IUD), and condoms for contraception. Of five women diagnosed with AT deficiency while taking OCPs, three switched to an IUD, one to condoms, and one used no alternative method. Eighteen women reported 42 total pregnancies, with 33 (79%) resulting in live term birth, 3 (7%) in live preterm birth, and 6 (14%) in spontaneous abortion at a median of 12 weeks. Four (22%) women reported the use of anticoagulation during pregnancy. Eleven (61%) women reported menorrhagia and 4 (36%), while on anticoagulation for VTE events. Ten of 18 women (56%) reported that the diagnosis of AT had affected their reproductive health in some way., Conclusion: Women with AT deficiency require careful multidisciplinary management to avoid complications in the setting of contraception and pregnancy. AT deficiency impacts women's reproductive health experiences and patient-oriented reproductive decision-making is key.

Background: Certain diseases can occur with and without a trigger. We use Venous Thromboembolism (VTE) as our example to identify genetic interaction with pregnancy in women with VTE during pre- or postpartum. Pregnancy is one of the major risk factors for VTE as it accounts for 10% of maternal deaths., Methods: We performed a whole genome association analysis using the Cox Proportional Hazard (CoxPH) model adjusted for covariates to identify genetic variants associated with the time-to-event of VTE related to pre- or postpartum during the childbearing age of 18-45 years using a case-only design in a cohort of women with VTE. Women with a VTE event after 45 years of age were censored and contributed only follow-up time., Results: We identified two intragenic single nucleotide polymorphisms (SNPs) at genome-wide significance in the PURB gene located on chromosome 7, and two additional intragenic SNPs, one in the LINGO2 gene on chromosome 9 and one in RDXP2 on chromosome X., Conclusions: We showed that the time-to-event model is a useful approach for identifying potential hazard-modification of the genetic variants when the event of interest (VTE) occurs due to a risk factor (pre- or post-partum)., Competing Interests: The authors declare no conflict of interest.

Background: Reliable biomarkers predictive of venous thromboembolism (VTE) after acute trauma are uncertain. The objective of the study was to identify risk factors for symptomatic VTE after trauma, including individual plasma coagulome characteristics as reflected by thrombin generation., Methods: In a prospective, case-cohort study, trauma patients were enrolled over the 4.5-year period, 2011 to 2015. Blood was collected by venipuncture into 3.2% trisodium citrate at 0, 6, 12, 24, and 72 hours after injury and at hospital discharge. Platelet poor plasma was stored at -80 °C until analysis. Thrombin generation, as determined by the calibrated automated thrombogram (CAT) using 5 pM tissue factor (TF)/4 μM phospholipid (PS), was reported as peak height (nM thrombin) and time to peak height (ttPeak [minutes]). Data are presented as median [IQR] or hazard ratio with 95% CI., Results: Among 453 trauma patients (injury severity score = 13.0 [6.0, 22.0], hospital length of stay = 4.0 [2.0, 10.0] days, age = 49 [28, 64] years, 71% male, 96% with blunt mechanism, mortality 3.2%), 83 developed symptomatic VTE within 92 days after injury (35 [42%] after hospital discharge). In a weighted, multivariate Cox model that included clinical and CAT characteristics available within 24 hours of admission, increased patient age (1.35 [1.19,1.52] per 10 years, p < 0.0001), body mass index ≥30 kg/m (4.45 [2.13,9.31], p < 0.0001), any surgery requiring general anesthesia (2.53 [1.53,4.19], p = 0.0003) and first available ttPeak (1.67 [1.29, 2.15], p < 0.00001) were independent predictors of incident symptomatic VTE within 92 days after trauma (C-statistic = 0.799)., Conclusion: The individual's plasma coagulome (as reflected by thrombin generation) is an independent predictor of VTE after trauma. Clinical characteristics and ttPeak can be used to stratify acute trauma patients into high and low risk for VTE., Level of Evidence: Prognostic, level III.

The annual number of US venous thromboembolism (VTE) events, the number of potentially preventable events, and the effect of hospitalization-based prophylaxis are uncertain. We estimated VTE attack (incident plus recurrent VTE) rates and the total annual number of US VTE events related and unrelated to hospitalization using Rochester Epidemiology Project resources to identify all Olmsted County, Minnesota, residents with incident or recurrent VTE over the 6-year period 2005-2010. The average annual VTE attack rates related and unrelated to hospitalization were 282 and 8 per 10 000 person-years, respectively. The estimated average number of US VTE events was 495 669 per year (48% unrelated to hospitalization). Among Olmsted County residents hospitalized at a Mayo Clinic hospital from 2005 to 2010, the proportion of patients receiving VTE prophylaxis or with an indication that prophylaxis was unnecessary increased from ∼40% in 2005 to ∼90% by 2010. The annual age- and sex-adjusted hospitalization-related (in-hospital) VTE attack rates from 2005 to 2010 ranged from 251 to 306 (1155 to 1751) per 10 000 person-years (bed-years) and did not change significantly. The median durations of hospitalization and in-hospital prophylaxis were 3 days and 70 hours, respectively. A total of 75% of VTE events occurred after hospital discharge, with a 19.5-day median time to VTE. Additional efforts are needed to identify the individual inpatient and outpatient at high risk for incident and recurrent VTE and target (longer duration) primary and secondary prophylaxis to high-risk individuals who would benefit most., (© 2017 by The American Society of Hematology.)

Observational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P < 0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95% CI 1.02-1.12, P = 0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR = 1.59, 95% CI 1.30-1.93 per standard deviation increase in BMI, P = 5.8 × 10 -6 ). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.

To identify novel single nucleotide polymorphisms (SNPs) associated with venous thromboembolism (VTE) in African-Americans (AAs), we performed a genome-wide association study (GWAS) of VTE in AAs using the Electronic Medical Records and Genomics (eMERGE) Network, comprised of seven sites each with DNA biobanks (total ~39,200 unique DNA samples) with genome-wide SNP data (imputed to 1000 Genomes Project cosmopolitan reference panel) and linked to electronic health records (EHRs). Using a validated EHR-driven phenotype extraction algorithm, we identified VTE cases and controls and tested for an association between each SNP and VTE using unconditional logistic regression, adjusted for age, sex, stroke, site-platform combination and sickle cell risk genotype. Among 393 AA VTE cases and 4,941 AA controls, three intragenic SNPs reached genome-wide significance: LEMD3 rs138916004 (OR=3.2; p=1.3E-08), LY86 rs3804476 (OR=1.8; p=2E-08) and LOC100130298 rs142143628 (OR=4.5; p=4.4E-08); all three SNPs validated using internal cross-validation, parametric bootstrap and meta-analysis methods. LEMD3 rs138916004 and LOC100130298 rs142143628 are only present in Africans (1000G data). LEMD3 showed a significant differential expression in both NCBI Gene Expression Omnibus (GEO) and the Mayo Clinic gene expression data, LOC100130298 showed a significant differential expression only in the GEO expression data, and LY86 showed a significant differential expression only in the Mayo expression data. LEMD3 encodes for an antagonist of TGF-β-induced cell proliferation arrest. LY86 encodes for MD-1 which down-regulates the pro-inflammatory response to lipopolysaccharide; LY86 variation was previously associated with VTE in white women; LOC100130298 is a non-coding RNA gene with unknown regulatory activity in gene expression and epigenetics.

Reasons for trends in venous thromboembolism (VTE) incidence are uncertain. It was our objective to determine VTE incidence trends and risk factor prevalence, and estimate population-attributable risk (PAR) trends for each risk factor. In a population-based cohort study of all residents of Olmsted County, Minnesota from 1981-2010, annual incidence rates were calculated using incident VTE cases as the numerator and age- and sex-specific Olmsted County population estimates as the denominator. Poisson regression models were used to assess the relationship of crude incidence rates to year of diagnosis, age at diagnosis, and sex. Trends in annual prevalence of major VTE risk factors were estimated using linear regression. Poisson regression with time-dependent risk factors (person-years approach) was used to model the entire population of Olmsted County and derive the PAR. The age- and sex-adjusted annual VTE incidence, 1981-2010, did not change significantly. Over the time period, 1988-2010, the prevalence of obesity, surgery, active cancer and leg paresis increased. Patient age, hospitalisation, surgery, cancer, trauma, leg paresis and nursing home confinement jointly accounted for 79 % of incident VTE; obesity accounted for 33 % of incident idiopathic VTE. The increasing prevalence of obesity, cancer and surgery accounted in part for the persistent VTE incidence. The PAR of active cancer and surgery, 1981-2010, significantly increased. In conclusion, almost 80 % of incident VTE events are attributable to known major VTE risk factors and one-third of incident idiopathic VTE events are attributable to obesity. Increasing surgery PAR suggests that concurrent efforts to prevent VTE may have been insufficient.

Essentials We evaluated antibody status, thromboembolism and survival after cardiac surgery. Positive antibody tests are common - over 50% are seropositive at 30 days. Seropositivity did not increase thromboembolism or impair survival after cardiac surgery. Results show heparin induced thrombocytopenia antibody screening after surgery is not warranted., Summary: Background Heparin-induced thrombocytopenia (HIT) is a prothrombotic response to heparin therapy with platelet-activating, anti-platelet factor 4 (PF4)/heparin antibodies leading to thrombocytopenia associated with thromboembolism. Objective We tested the hypothesis that anti-PF4/heparin antibodies are associated with thromboembolism after cardiac surgery. Methods This multicenter, prospective cohort study collected laboratory and clinical data up to 30 days after surgery and longer-term clinical follow-up data. The primary outcome variable combined new arterial or venous thromboembolic complications (TECs) with all-cause death until 90 days after surgery. Laboratory analyses included platelet counts and anti-PF4/heparin antibody titers (GTI ELISA), with a confirmatory excess heparin step and serotonin release assay. Chi-square testing was used to test the relationship between our outcome and HIT antibody seropositivity. Results Initially, 1021 patients were enrolled between August 2006 and May 2009, and follow-up was completed in December 2014. Seropositivity defined by OD > 0.4 was common, being almost 20% preoperatively, > 30% by discharge, and > 60% by day 30. Death (1.7% within 30 days) or TECs (69 in total) were more likely if the partient was seronegative (OD < 0.4), but positivity defined by OD > 1.0 or including an excess heparin confirmatory step resulted in equal incidence of death or TECs, whether the patient was seronegative or seropositive. Incorporating the serotonin release assay for platelet-activating antibodies did not alter these findings. Conclusions Seropositivity for anti-PF4/heparin antibodies does not increase the risk of death or thromboembolism after cardiac surgery. Screening is not indicated, and seropositivity should only be interpreted in the context of clinical evidence for HIT., Trial Registration: Duke IRB Protocol #00010736., Competing Interests: of Conflict of Interests The authors state that they have no conflict of interest., (© 2016 International Society on Thrombosis and Haemostasis.)

Purpose: The purpose of this study is to estimate medical costs attributable to venous thromboembolism among patients with active cancer., Methods: In a population-based cohort study, we used Rochester Epidemiology Project (REP) resources to identify all Olmsted County, Minn. residents with incident venous thromboembolism and active cancer over the 18-year period, 1988-2005 (n = 374). One Olmsted County resident with active cancer without venous thromboembolism was matched to each case on age, sex, cancer diagnosis date, and duration of prior medical history. Subjects were followed forward in REP provider-linked billing data for standardized, inflation-adjusted direct medical costs from 1 year prior to index (venous thromboembolism event date or control-matched date) to the earliest of death, emigration from Olmsted County, or December 31, 2011, with censoring on the shortest follow-up to ensure a similar follow-up duration for each case-control pair. We used generalized linear modeling to predict costs for cases and controls and bootstrapping methods to assess uncertainty and significance of mean adjusted cost differences. Outpatient drug costs were not included in our estimates., Results: Adjusted mean predicted costs were 1.9-fold higher for cases ($49,351) than for controls ($26,529) (P < .001) from index to up to 5 years post index. Cost differences between cases and controls were greatest within the first 3 months (mean difference = $13,504) and remained significantly higher from 3 months to 5 years post index (mean difference = $12,939)., Conclusions: Venous thromboembolism-attributable costs among patients with active cancer contribute a substantial economic burden and are highest from index to 3 months, but may persist for up to 5 years., Competing Interests: All authors report no conflict of interest., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Appropriate periprocedural management of the chronically anticoagulated patient with an inherited or acquired thrombophilia is uncertain. The objective of this study was to test "thrombophilia" as a potential predictor of the 3-month cumulative incidence of thromboembolism and major bleeding among chronically anticoagulated patients undergoing an invasive procedure., Methods: In a prospective cohort study, consecutive chronically anticoagulated patients referred to the Mayo Thrombophilia Center for standardized periprocedural anticoagulation management who had venous thromboembolism and complete thrombophilia testing were categorized as "severe," "non-severe," or "no identifiable" thrombophilia. The 3-month cumulative incidence rates of thromboembolism, bleeding, and death were estimated using the Kaplan-Meier product limit method., Results: Among 362 patients with complete thrombophilia testing, 165 (46%) had a defined thrombophilia; 76 patients had severe thrombophilia, mainly due to antiphospholipid syndrome (66%). Half of the patients in each of the 3 groups received pre- and postprocedure heparin. During follow-up, there were no thromboembolic events, rare major bleeding events (1% for each group), and 4 deaths. Due to the very low event rates for each of these outcomes, Cox proportional hazard modeling could not be performed., Conclusions: Periprocedural event rates were low irrespective of thrombophilia status. Inherited or acquired thrombophilia was not a predictor of thromboembolism, major bleeding, or mortality after temporary interruption of chronic anticoagulation for an invasive procedure., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Predictors of venous thromboembolism (VTE) after trauma are uncertain., Objective: To identify independent predictors of VTE after acute trauma., Methods: Using Rochester Epidemiology Project (REP) resources, we identified all Olmsted County, MN residents with objectively-diagnosed incident VTE within 92days after hospitalization for acute trauma over the 18-year period, 1988-2005. We also identified all Olmsted County residents hospitalized for acute trauma over this time period and chose one to two residents frequency-matched to VTE cases on sex, event year group and ICD-9-CM trauma code predictive of surgery. In a case-cohort study, demographic, baseline and time-dependent characteristics were tested as predictors of VTE after trauma using Cox proportional hazards modeling., Results: Among 200 incident VTE cases, the median (interquartile range) time from trauma to VTE was 18 (6, 41) days. Of these, 62% cases developed VTE after hospital discharge. In a multiple variable model including 370 cohort members, patient age at injury, male sex, increasing injury severity as reflected by the Trauma Mortality Prediction Model (TMPM) Mortality Score, immobility prior to trauma, soft tissue leg injury, and prior superficial vein thrombosis were independent predictors of VTE (C-statistic=0.78)., Conclusions: We have identified clinical characteristics which can identify patients at increased risk for VTE after acute trauma, independent of surgery. Almost two thirds of all incident VTE events occurred after initial hospital discharge (18day median time from trauma to VTE) which questions current practice of not extending VTE prophylaxis beyond hospital discharge., Competing Interests: All authors report no conflict of interest., (Copyright © 2016. Published by Elsevier Ltd.)