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Background Predictors of venous thromboembolism ( VTE ) recurrence are uncertain. Objective To identify predictors of VTE recurrence, adjusted for treatments and interim exposures. Materials and Methods Using Rochester Epidemiology Project resources, all Olmsted County, MN residents with objectively-diagnosed incident VTE over the 13-year period, 1988–2000, who survived ≥ 1 day were followed for first objectively-diagnosed VTE recurrence. For all patients with recurrence, and a random sample of all surviving incident VTE patients (n = 415), we collected demographic and baseline characteristics, treatments and interim exposures. In a case-cohort study design, demographic, baseline, treatment and interim exposure characteristics were tested as potential predictors of VTE recurrence using time-dependent Cox proportional hazards modeling. Results Among 1262 incident VTE patients, 306 developed recurrence over 6,440 person-years. Five-year recurrence rates, overall and for cancer-associated, idiopathic and non-cancer secondary VTE, were 24.5%, 43.4%, 27.3% and 18.1%, respectively. In multivariable analysis, interim hospitalization, active cancer, pregnancy, central venous catheter and respiratory infection were associated with increased hazards of recurrence, and warfarin and aspirin were associated with reduced hazards. Adjusting for treatments and these interim risk factors, male sex, baseline active cancer and failure to achieve a therapeutic aPTT in the first 24 hours were independently associated with increased hazards of VTE recurrence over the entire follow-up period, while the hazards of recurrence for patient age, chronic lung disease, leg paresis, prior superficial vein thrombosis and idiopathic VTE varied over the follow-up period. Conclusions Baseline and interim exposures can stratify VTE recurrence risk and may be useful for directing secondary prophylaxis. [ABSTRACT FROM AUTHOR]

Background We estimated medical costs attributable to venous thromboembolism (VTE) among patients currently or recently hospitalized for major operation. Methods Using Rochester Epidemiology Project resources, we identified all Olmsted County, MN, residents with objectively diagnosed incident VTE within 92 days of hospitalization for major operation during an 18-year period, 1988–2005 ( n = 355). One Olmsted County resident hospitalized for major operation without VTE was matched to each case on event date (±1 year), type of operation, duration of previous medical history, and active cancer status. Subjects were followed in Rochester Epidemiology Project provider-linked billing data for standardized, inflation-adjusted direct medical costs from 1 year before index (case's VTE event date and control's matched date) to earliest of death, emigration, or December 31, 2011. We used generalized linear modeling to predict costs for cases and controls and used bootstrapping methods to assess uncertainty and significance of mean adjusted cost differences. Results Adjusted mean predicted costs were more than 1.5-fold greater for cases ($55,956) than for controls ($32,718) ( P ≤ .001) from index to up to 5 years postindex. Cost differences between cases and controls were greatest within the first 3 months after index (mean difference = $12,381). Costs were greater for cases than controls (mean difference = $10,797) from 3 months to up to 5 years postindex and together accounted for about half of the overall cost difference. Conclusion VTE during or after recent hospitalization for major operation contributes a substantial economic burden; VTE-attributable costs are greatest in the initial 3 months but persist for up to 5 years. [ABSTRACT FROM AUTHOR]

Background: Major trauma is an independent risk factor for developing venous thromboembolism. While increases in thrombin generation and/or procoagulant microparticles have been detected in other patient groups at greater risk for venous thromboembolism, such as cancer or coronary artery disease, this association has yet to be documented in trauma patients. This pilot study was designed to characterize and quantify thrombin generation and plasma microparticles in individuals early after traumatic injury. Methods: Blood was collected in the trauma bay from 52 blunt injured patients (cases) and 19 uninjured outpatients (controls) and processed to platelet poor plasma to allow for (1) isolation of microparticles for identification and quantification by flow cytometry, and (2) in vitro thrombin generation as measured by calibrated automatic thrombography. Data collected are expressed as either mean ± standard deviation or median with interquartile range. Results: Among the cases, which included 39 men and 13 women (age, 40 ± 17 years), the injury severity score was 13 ± 11, the international normalized ratio was 1.0 ± 0.1, the thromboplastin time was 25 ± 3 seconds, and platelet count was 238 ± 62 (thousands). The numbers of total (cell type not specified) procoagulant microparticles, as measured by Annexin V staining, were increased compared to nontrauma controls (541 ± 139/μL and 155 ± 148/μL, respectively; P < .001). There was no significant difference in the amount of thrombin generated in trauma patients compared to controls; however, peak thrombin was correlated to injury severity (Spearman correlation coefficient R, 0.35; P = .02). Conclusion: Patients with blunt trauma have greater numbers of circulating procoagulant microparticles and increased in vitro thrombin generation. Future studies to characterize the cell-specific profiles of microparticles and changes in thrombin generation kinetics after traumatic injury will determine whether microparticles contribute to the hypercoagulable state observed after injury. [Copyright &y& Elsevier]

Abstract: Introduction: Because the risk of venous thromboembolism (VTE) associated with progestin is uncertain, we tested oral contraceptives, estrogen and progestin as independent VTE risk factors. Materials and Methods: Using longitudinal, population-based Rochester Epidemiology Project resources, we identified all Olmsted County, MN women with objectively-diagnosed incident VTE over the 13-year period, 1988-2000 (n=726) and one to two Olmsted County women per case matched on age, event year and duration of prior medical history (n=830), and reviewed their complete medical history in the community for previously-identified VTE risk factors (i.e., hospitalization with or without surgery, nursing home confinement, trauma/fracture, leg paresis, active cancer, varicose veins and pregnancy/postpartum), and oral contraceptive, oral estrogen, and oral or injectable progestin exposure. Using conditional logistic regression we tested these hormone exposures as VTE risk factors, both unadjusted and after adjusting for previously-identified VTE risk factors. Results: In unadjusted models, oral contraceptives, progestin alone, and estrogen plus progestin were significantly associated with VTE. Individually adjusting for body mass index (BMI) and previously-identified VTE risk factors, these effects remained essentially unchanged except that progestin alone was not associated with VTE after adjusting for active cancer. Considering only case-control pairs without active cancer, progestin alone was positively but non-significantly associated with VTE (OR=2.49; p=0.16). Adjusting for BMI and previously-identified VTE risk factors including active cancer, oral contraceptives, estrogen alone, and progestin with or without estrogen were significantly associated with VTE. Conclusions: Oral contraceptives, estrogen alone, estrogen plus progestin, and progestin with or without estrogen are independent VTE risk factors. [Copyright &y& Elsevier]

Objective: The purpose of this study was to determine the usefulness of a simple screening tool for bleeding disorders in a multisite population of women with menorrhagia. Study Design: Women with menorrhagia between the ages of 18 and 50 years from 6 geographically diverse US centers underwent hemostatic testing for bleeding disorders, complete blood cell count, and ferritin. A questionnaire that contained all elements of the 8-question screening tool was administered. Sensitivity of the screening tool, a screening tool with a pictorial blood assessment chart (PBAC) score of >185, and a screening tool with serum ferritin were calculated for hemostatic disorders. Results: Two hundred and seventeen women who were identified with a PBAC score of ≥100 participated in the study. The sensitivity of the screening tool was 89% for hemostatic defects, and sensitivity increased to 93% and 95% with a serum ferritin level of ≤20 ng/mL and a PBAC score of >185, respectively. Conclusion: This study confirms the usefulness of a short screening tool for the stratification of women with menorrhagia for hemostatic evaluation. [ABSTRACT FROM AUTHOR]

Abstract: 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 β predominates in circulating platelets. Estrogenic treatment in ovariectomized animals decreased platelet aggregation and adenosine triphosphate (ATP) secretion. However, acute exposure to 17β-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. [Copyright &y& Elsevier]

Abstract: Rationale: Analyses of circulating cell membrane-derived microvesicles (MV) have come under scrutiny as potential diagnostic and prognostic biomarkers of disease. However, methods to isolate, label and quantify MV have been neither systematized nor validated. Objective: To determine how pre-analytical, analytical and post-analytical factors affect plasma MV counts, markers for cell of origin and expression of procoagulant surface phosphatidylserine. Methods and results: Peripheral venous blood samples were collected from healthy volunteers and patients with cardiovascular disease and/or diabetes. Effects of blood sample collection, anticoagulant and sample processing to platelet free plasma (PFP), and MV isolation, staining and storage (freeze–thaw) and cytometer design were evaluated with replicate samples from these populations. The key finding is that use of citrate or EDTA anticoagulants decreases or eliminates microvesicles from plasma by inducing adhesion of the microvesicles to platelets or other formed elements. Protease inhibitor anticoagulants, including heparin, preserve MV counts. A centrifugation protocol was developed in which recovery of isolated MV was high with resolution down to the equivalent light scatter of 0.2μm latex beads. Each procedure was systematically evaluated for its impact on the MV counts and characteristics. Conclusion: This study provides a systematic methodology for MV isolation, identification and quantification, essential for development of MV as diagnostic and prognostic biomarkers of disease. [Copyright &y& Elsevier]

Abstract: Introduction: Electrophoretic analysis of plasma von Willebrand factor (VWF) multimer distribution and infrastructure is essential for subtyping von Willebrand disease. To improve the sensitivity, precision and efficiency of this assay, we developed and validated a new in-gel infrared fluorescent VWF multimer imaging method to visualize and quantify VWF multimers directly in the agarose gel, thus eliminating electroblotting or autoradiographic steps. Materials/Methods: VWF multimer analyses of plasma samples from 34 patients with known von Willebrand disease or acquired von Willebrand syndrome, 9 patients with acquired VWF abnormalities, 26 normal volunteer donors and 49 patient samples referred for von Willebrand factor multimer analysis were performed by both traditional autoradiographic and the new infra-red imaging methods and compared. VWF multimer image data were electronically acquired, archived and analyzed. Results: The in-gel infrared method has a sensitivity of detecting VWF antigen as low as approximately 1.6IU/dL, a reliable fluorescent intensity with intra- and inter-day variability (CV) of 5% and 6% respectively, and provides superior imaging resolution and shortened test turnaround time. Using intermediate resolution agarose gel electrophoresis, the infra-red method sensitively detects subtle loss of highest molecular weight von Willebrand factor multimers in plasmas with acquired VWF abnormalities and in commercial normal reference plasmas, and provides evidence of increased proteolysis of ultralarge multimers in some type 2 VWD plasmas. Conclusions: The in-gel infrared fluorescent VWF multimer imaging method provides a sensitive, reliable, efficient and robust system to improve laboratory testing for von Willebrand disease classification. [ABSTRACT FROM AUTHOR]

Abstract: Post-menopausal hormone therapy increases the risk for venous thrombosis, and possibly myocardial infarction (MI) and ischemic stroke. However, most women using hormone therapy do not suffer thrombosis, and to date our ability to identify women at risk is limited. Thrombosis, arterial or venous, has 2 requisites: a vascular anomaly and a response of the hemostasis system to the anomaly. Consequently, experimental approaches to understand the pathophysiology of thrombosis require definition of vascular anatomy and function as well as characteristics of the blood within the context of genetic background, lifestyle choices and environmental exposures, which influence gene expression. Defining interactions among factors that affect individual propensity to thrombosis will allow physicians to better identify at-risk individuals, for example a woman contemplating estrogen therapy for symptoms of menopause, and prevent adverse thrombotic events. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Cardiovascular disease (CVD) has been reported to be on the increase in the American Indian/Alaska Native (AI/AN) population. The Indian Health Service (IHS) hospital discharge database was used to describe venous thromboembolism (VTE)-associated hospitalizations among patients receiving IHS-reported medical care in the United States from 1980 through 1996. The average overall VTE-associated hospitalization rate in the AI/AN population during 1980–1996 was 33.1 per 100,000, however, the rate significantly decreased from 38.4 per 100,000 AI/ANs in 1980–1982 to 33.2 in 1994–1996. The average age at hospitalization was 50.4 years, which was consistent during the 17-year period. The overall annual VTE hospitalization rate was higher for females than for males (38.0 versus 27.7 per 100,000). The female VTE hospitalization rates decreased significantly from 46.1 per 100,000 in 1980–1982 to 36.7 per 100,000 in 1994–1996 (risk ratio: RR=1.3; 95% confidence interval: CI=1.1–1.4), while the rates for males remained unchanged. The VTE hospitalization rates also varied by geographic region. The hospitalization rate was highest in the East region (52.2 per 100,000) and lowest in the Alaska region (16.1 per 100,000). These data indicate that the overall VTE rate for AI/ANs may not have only decreased, but appears lower than the reported rate for Caucasians. [Copyright &y& Elsevier]

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 92 days 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 (18 day median time from trauma to VTE) which questions current practice of not extending VTE prophylaxis beyond hospital discharge. [ABSTRACT FROM AUTHOR]

Background Independent risk factors for cancer-associated incident venous thromboembolism (VTE) and their magnitude of risk are not fully characterized. Aim To identify non-cancer and cancer-specific risk factors for cancer-associated incident VTE. Methods In a population-based retrospective case–control study, we used Rochester Epidemiology Project and Mayo Clinic Cancer Registry resources to identify all Olmsted County, MN residents with active cancer-associated incident VTE, 1973–2000 (cases; n = 570) and 1–3 residents with active cancer matched to each case on age, sex, date and duration of active cancer (controls; n = 604). Using conditional logistic regression, we tested cancer and non-cancer characteristics for an association with VTE, including a cancer site VTE risk score. Results In the multivariable model, higher cancer site VTE risk score (OR = 1.4 per 2-fold increase), cancer stage ≥ 2 (OR = 2.2), liver metastasis (OR = 2.7), chemotherapy (OR = 1.8) and progesterone use (OR = 2.1) were independently associated with VTE, as were BMI < 18.5 kg/m 2 (OR = 1.9) or ≥ 35 kg/m 2 (OR = 4.0), hospitalization (OR = 7.9), nursing home confinement (OR = 4.7), central venous (CV) catheter (OR = 8.5) and any recent infection (OR = 1.7). In a subgroup analysis, platelet count ≥ 350 × 10 9 /L at time of cancer diagnosis was marginally associated with VTE (OR = 2.3, p = 0.07). Conclusion Cancer site, cancer stage ≥ 2, liver metastasis, chemotherapy, progesterone, being underweight or obese, hospitalization/nursing home confinement, CV catheter, and infection are independent risk factors for incident VTE in active cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to examine the differences in commonly associated characteristics and risk factors of venous thromboembolism (VTE) between patients with and without cancer in a VTE population. Materials and Methods: Uniform data were collected for patients with a diagnosis of VTE obtaining care at CDC funded Thrombosis Network Centers. Patient characteristics and risk factors were compared in VTE patients with and without cancer. Logistic regression was used to calculate the unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) to assess patient characteristics and thrombotic risk factors more frequently identified among VTE patients with cancer compared to those without cancer. Results: Between August 2003 and April 2011, 3,115 adult patients with a diagnosis of VTE including 189 (6.1%) patients with active cancer participated in the multi-site thrombosis registry. VTE patients with cancer had a higher prevalence of PE and DVT in unusual sites compared to those without cancer. Thrombophilia was more common among VTE patients without cancer than those with cancer (25.1% vs 10.6%, p < 0.001). In adjusted analysis, age group ≥ 45 years (OR = 5.20, 95% CI, 3.30, 8.18), surgery (OR = 1.86, 95% CI, 1.19, 2.91), and hypertension (OR = 1.66, 95% CI, 1.15, 2.40) were the VTE risk factors more commonly found among VTE patients with cancer. Conclusion: The study identified several thrombotic risk factors more likely to be found with cancer associated VTE, which may help to characterize at risk cancer patients and to develop prevention and management strategies in this population. [ABSTRACT FROM AUTHOR]

Introduction Recurrent venous thromboembolism (VTE) occurs infrequently following a provoked event but occurs in up to 30% of individuals following an initial unprovoked event. There is limited understanding of the biological mechanisms that predispose patients to recurrent VTE. Objectives To identify whole blood gene expression profiles that distinguished patients with clinically distinct patterns of VTE. Patients/Methods We studied 107 patients with VTE separated into 3 groups: (1) 'low-risk' patients had one or more provoked VTE; (2) 'moderate-risk' patients had a single unprovoked VTE; (3) 'high-risk' patients had ≥ 2 unprovoked VTE. Each patient group was also compared to twenty-five individuals with no personal history of VTE. Total RNA from whole blood was isolated and hybridized to Illumina HT-12 V4 Beadchips to assay whole genome expression. Results Using class prediction analysis, we distinguished high-risk patients from low-risk patients and healthy controls with good receiver operating curve characteristics (AUC = 0.81 and 0.84, respectively). We also distinguished moderate-risk individuals and low-risk individuals from healthy controls with AUC's of 0.69 and 0.80, respectively. Using differential expression analysis, we identified several genes previously implicated in thrombotic disorders by genetic analyses, including SELP, KLKB1, ANXA5, and CD46 . Protein levels for several of the identified genes were not significantly different between the different groups. Conclusion Gene expression profiles are capable of distinguishing patients with different clinical presentations of VTE, and genes relevant to VTE risk are frequently differentially expressed in these comparisons. Highlights • Gene expression was used to study 3 groups with VTE and healthy controls. • Recurrent unprovoked VTE patients were distinguished from those with provoked VTE. • Patients with recurrent unprovoked VTE were also distinguished from controls. • Genes specific to coagulation, and immune response were differentially expressed. • Seven genes involved in complement activation were also differentially expressed. [ABSTRACT FROM AUTHOR]

Background The risk of venous thromboembolism (VTE) by cancer site is uncertain. ObjectiveTo estimate VTE risk by tumor site. Methods We enumerated observed active cancers by cancer site for Olmsted County, MN residents with incident VTE over the 13-year period, 1988-2000 (n=345 of 1417). We used 1988-2000 Iowa State Surveillance, Epidemiology, and End Results (SEER) data to estimate the expected age-specific prevalence of cancer by cancer site for all VTE cases; standardized Morbidity Ratios (SMR) for each cancer site were estimated by dividing the observed number of cancers in the VTE incident cohort by the expected number. Relative risk regression was used to model the observed number of cancers of each site, adjusting for the expected value based on SEER prevalence data, using generalized linear regression with a Poisson error and the natural log of the age- and sex-group expected count as an offset. Results For men and women with VTE, all cancer sites had an increased SMR, ranging from 4.1 for head neck cancer to 47.3 for brain cancer. Among women, the SMR for breast, ovarian and other gynecologic cancers were 8.4, 13.0 and 8.4, respectively; for men, prostate cancer SMR was 7.9. Adjusting for age and sex, the relative risk (RR) of cancer in VTE cases was associated with cancer site in a multivariable model (p<0.001). Adjusting for age and sex, pancreatic, brain, other digestive cancers, and lymphoma had significantly higher RRs than the grouped comparison cancers. Conclusions Incident VTE risk can be stratified by cancer site. [ABSTRACT FROM AUTHOR]

Background While post thrombotic syndrome (PTS) is increasingly recognized as a frequent and potentially serious complication of deep vein thrombosis (DVT) in children, limited information is available regarding predictors of PTS. Methods Using the Mayo Clinic Master Diagnostic Index, all pediatric patients (age 0 to 18years) with a potential DVT based on ICD-8 codes over the 15-year period, 1995 to 2009 were identified. A validated PTS survey instrument was mailed to eligible patients followed by a second mailing and three reminder phone calls for non-responders. Baseline clinical and radiographic characteristics were abstracted from patient medical records and tested as potential predictors of PTS using logistic regression. Associations were summarized by calculating odds ratios (OR) and corresponding 95% confidence intervals. Results Ninety patients agreed to participate. The mean age (± SD) at DVT diagnosis and survey completion were 12.8 (± 6.1) and 19.3 (± 7.7) years, respectively. Fifty three respondents (59%) reported mild PTS whereas 12 (13%) reported moderate-to-severe PTS. Pain (34%) and dilated blood vessels (40%) were the most frequent PTS symptom and sign, respectively. On multivariate analysis, predictors of PTS included duration between incident DVT and survey completion (OR 1.75; 95% CI: 1.08 - 2.84) and number of thrombosed vein segments (OR 1.40; 95% CI: 1.05 - 1.86). Conclusion Over 70% of children with DVT report subsequent symptoms or signs of PTS, though only 13% report clinically significant, moderate-to-severe PTS. Number of thrombosed vein segments at diagnosis and time duration between incident DVT and survey completion were independent predictors of PTS. [ABSTRACT FROM AUTHOR]

Introduction Because the association of myocardial infarction (MI) and venous thromboembolism (VTE) is uncertain, we tested MI as a VTE risk factor and VTE as a predictor of MI. Materials and Methods Using Rochester Epidemiology Project resources, we identified all Olmsted County, MN residents with objectively-diagnosed incident VTE over the 13-year period, 1988-2000 (n = 1311), one to two resident controls per VTE case (n = 1511), and all residents with incident MI over the 31-year period, 1979-2010. For VTE cases and controls, we reviewed their complete medical records in the community for VTE and MI risk factors. Using conditional logistic regression we tested MI as a potential VTE risk factor, both unadjusted and after adjusting for VTE risk factors. We also followed VTE cases and controls without prior MI forward in time for incident MI through 12/31/2010, and using Cox proportional hazards modeling, tested VTE as a predictor of MI, both unadjusted and after adjusting for MI risk factors. Results The number (%) of MI prior to VTE among cases and controls were 75 (5.7) and 51 (3.4), respectively, and the number (%) of MI after VTE among cases and controls were 58 (4.4) and 77 (5.1), respectively. In univariate analyses, MI was significantly associated with VTE but not after adjusting for VTE risk factors. In both univariate and multivariate analyses, VTE (overall or idiopathic) was not a predictor of MI. Conclusions MI is not an independent risk factor for VTE, and VTE is not a predictor of MI. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Black women have an increased risk of adverse pregnancy outcomes and the characteristics of thrombotic risk factors in this population are unknown. The objective of this study was to examine the racial differences in thrombotic risk factors among women with adverse pregnancy outcomes. Methods: Uniform data were collected in women with adverse pregnancy outcomes (pregnancy losses, intrauterine growth restriction (IUGR), prematurity, placental abruption and preeclampsia) referred to Thrombosis Network Centers funded by the Centers for Disease Control and Prevention (CDC). Results: Among 343 white and 66 black women seen for adverse pregnancy outcomes, protein S and antithrombin deficiencies were more common in black women. The prevalence of diagnosed thrombophilia was higher among whites compared to blacks largely due to Factor V Leiden mutation. The prevalence of a personal history of venous thromboembolism (VTE) did not differ significantly by race. A family history of VTE, thrombophilia, and stroke or myocardial infarction (MI) was higher among whites. Black women had a higher body mass index, and a higher prevalence of hypertension, while the prevalence of sickle cell disease was approximately 27 fold higher compared to the general US black population. Conclusions: Thrombotic risk factors differ significantly in white and black women with adverse pregnancy outcomes. Such differences highlight the importance of considering race separately when assessing thrombotic risk factors for adverse pregnancy outcomes. [Copyright &y& Elsevier]

Abstract: Background/objectives: The most cost-effective periprocedural management of patients with mechanical heart valves (MHV) is uncertain. The objective was to compare the effectiveness, safety and costs for inpatient intravenous unfractionated heparin (IVUH) vs. outpatient low molecular weight heparin (LMWH) “bridging” as periprocedural anticoagulation management for MHV patients. Methods: In a case-cohort study, Olmsted County, MN residents with MHV who received outpatient periprocedural LMWH management (cases) over the 11-year period, 1997–2007, were matched to residents with MHV who received inpatient IVUH periprocedural management on valve location and type, and on procedure type. Patients were followed for 3months following hospitalization to identify thromboembolism (TE) and major bleeding. Total costs from 30days before to 90days after the procedure were determined from the Olmsted County Healthcare Expenditure and Utilization Database. Outcomes were compared using survival analysis and costs were compared using the Wilcoxon rank sum. Results: 149 cases (100 aortic, 29 mitral, 20 both; 64% bileaflet) were compared to 149 cohort members (100 aortic, 29 mitral, 20 both; 75% bileaflet). While the 3-month cumulative incidence of TE did not differ significantly among cases (2.7%) and cohort members (4.7%; p=0.36), major bleeding was significantly lower in cases (5.4% vs. 15.4%; p<0.005). Total costs were significantly higher for cohort members ($50,984 vs. $39,347; p=0.002) due to higher inpatient costs ($47,729 vs. $34,860; p=0.0002). Conclusions: Outpatient bridging LMWH therapy is equally effective, but safer and less costly than inpatient IVUH as periprocedural anticoagulation management for MHV patients. [Copyright &y& Elsevier]

OBJECTIVE: To create a cohort for cost-effective genetic research, the Mayo Genome Consortia (MayoGC) has been assembled with participants from research studies across Mayo Clinic with highthroughput genetic data and electronic medical record (EMR) data for phenotype extraction. PARTICIPANTS AND METHODS: Eligible participants include those who gave general research consent in the contributing studies to share high-throughput genotyping data with other investigators. Herein, we describe the design of the MayoGC, including the current participating cohorts, expansion efforts, data processing, and study management and organization. A genome-wide association study to identify genetic variants associated with total bilirubin levels was conducted to test the genetic research capability of the MayoGC. RESULTS: Genome-wide significant results were observed on 2q37 (top single nucleotide polymorphism, rs4148325; P=5.0 x 10-62) and 12p12 (top single nucleotide polymorphism, rs4363657; P=5.1 × 10-8) corresponding to a gene cluster of uridine 5′-diphospho-glucuronosyltransferases (the UGTL4 cluster) and solute carrier organic anion transporter family, member 1B1 (SLCO1B1), respectively. CONCLUSION: Genome-wide association studies have identified genetic variants associated with numerous phenotypes but have been historically limited by inadequate sample size due to costly genotyping and phenotyping. Large consortia with harmonized genotype data have been assembled to attain sufficient statistical power, but phenotyping remains a rate-limiting factor in gene discovery research efforts. The EMR consists of an abundance of phenotype data that can be extracted in a relatively quick and systematic manner. The MayoGC provides a model of a unique collaborative effort in the environment of a common EMR for the investigation of genetic determinants of diseases. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To test active cancer for an association with venous thromboembolism (VTE) location. PATIENTS AND METHODS: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN, residents with incident VIE during the 35-year period 1966-2000 (N=3385). We restricted analyses to residents with objectively diagnosed VIE during the 17-year period from January 1, 1984, to December 31, 2000 (N=1599). For each patient, we reviewed the complete medical records in the community for patient age, gender, and most recent body mass index at VIE onset; VIE event type and location; and previously identified independent VIE risk factors (ie, surgery, hospitalization for acute medical illness, active cancer, leg paresis, superficial venous thrombosis, and varicose veins). Using logistic regression we tested active cancer for an association with each of 4 symptomatic VIE locations (arm or intra-abdominal deep venous thrombosis [VI], intra-abdominal DVI, pulmonary embolism, and bilateral leg DVI), adjusted for age, gender, body mass index, and other VTE risk factors. RESULTS: In multivariate analyses, active cancer was independently associated with arm or intra-abdominal DVI (odds ratio [OR], 1.76; P=.01), Intra-abdominal DVI (OR, 2.22; P=.004), and bilateral leg DVI (OR, 2.09; P=.02), but not pulmonary embolism (OR, 0.93). CONCLUSION: Active cancer is associated with VIE location. Location of VIE may be useful in decision making regarding cancer screening. [ABSTRACT FROM AUTHOR]

The antithrombotic benefits of warfarin are countered by a narrow therapeutic index that contributes to excessive bleeding or cerebrovascular clotting and stroke In some patients. This article reviews the current literature describing warfarin sensitivity genotyping and compares the results of that review to the findings of our study in 189 patients at Mayo Clinic conducted between June 2001 and April 2003. For the review of the iiterature, we identified relevant peer-reviewed articles by searching the Web of Knowledge using key word warfarin-related adverse event. For the 189 Mayo Clinic patients initiating warfarin therapy to achieve a target International normalized ratio (INR) in the range of 2.0 to 3.5, we analyzed the CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genetic loci to study the relationship among the Initial warfarin dose, steady-state dose, time to achieve steady-state dose, variations in 1NR, and allelic variance. Results were compared with those previously reported In the literature for 637 patients. The relationships between allelic variants and warfarin sensitIvity found in our study of Mayo Clinic patients are fundamentally the same as In those reported by others. The Mayo Clinic population is predominantly white and shows considerable allelic variability in CYP2C9 and VKORC1. Certain of these alleles are associated with Increased sensitivity to warfarin Polymorphisms in CYP2C9 and VKORC1 have a considerable effect on warfarin dose In white people. A correlation between steady-state warfarin dose and allelic variants of CYP2C9 and VKORC1 has been demonstrated by many previous reports and is reconfirmed in this report. The allelic variants found to most affect warfarin sensitivity are CYP2C9*1*1- VKORC1BB (less warfarin sensitivity than typical); CYP2C9*1*1. VKORC1AA (considerable variance in INR throughout initiation); CYP2C9*1*2-VKORC1AB (more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C9*1*2-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1AA (much more sensitivity to warfarin than typical); and CYP2C9*2*2-VKORC2AB (much more sensitivity to warfarin than typical). Although we were unable to show an association between allelic variants and initial warfarin dose or dose escalation, an association was seen between allelic variant and steady-state warfarin dose. White people show considerable variance in CYP2C9 allele types, whereas people of Asian or African descent Infrequently carry CYP2C9 allelic variants. The VKORC1AA allele associated with high warfarin sensitivity predominates in those of Asian descent, whereas white people and those of African descent show diversity, carrying either the VKORC1BB, an allele associated with low warfarin sensitivity, or VKORC1AB or VKORC1AA, alleles associated with moderate and high warfarin sensitivity, respectively. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: To estimate the three-month cumulative incidence of thromboembolism and bleeding among mechanical heart valve (MHV) patients receiving peri-procedural anticoagulation management, consecutive MHV patients referred to the Mayo Clinic Thrombophilia Center for peri-procedural anticoagulation management over the seven-year period, 1997-2003, were followed for three months for thromboembolism, bleeding and vital status. Materials and Methods: Warfarin was stopped 4-5 days prior to the procedure, and re-started after the procedure as soon as hemostasis was assured. The decision to provide bridging therapy with low molecular weight (LMWH) or unfractionated (UFH) heparin was individualized and based on the estimated risks of TE and bleeding. Results: 556 MHV patients (372 aortic only, 136 mitral only, 48 with multiple valves) underwent 580 procedures. The three-month cumulative incidence of thromboembolism was 0.9% which included: cerebral ischemia (n=3), unstable angina (n=1), acute myocardial infarction (n=1). None were fatal. The cumulative incidence of major bleeding was 3.6% and fatal in 0.2%. The incidence of major bleeding events did not differ by postoperative anticoagulant strategy whether LMWH (3.7%), UFH (6.1%), or no heparin (2.4%) was used (p=0.26). Conclusions: The three-month cumulative incidence of thromboembolism among MHV patients in whom anticoagulation is temporarily interrupted for an invasive procedure is low. Whereas bleeding exceeds thromboembolic complications, our current practice is to restart warfarin as soon as possible post-procedure. Post-procedural heparin use is reserved for patients with the highest thromboembolic risk (mitral MHV, multiple MHVs, MHV with prior stroke or atrial fibrillation) waiting at least 48 hours before initiating. [Copyright &y& Elsevier]

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 risk factors for venous thromboemboilsm (VIE) among nursing home (NH) residents. PARTICIPANTS AND METHODS: This population-based historical cohort study used Minnesota Case Mix Review Program (MCMRP) Public Research Flies 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 VIE 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 VIE diagnosis (ie, index assessment). Cases and controls were compared for preindex assessment characteristics. Accuracy of MCMRP VIE ascertainment was explored by comparing MCMRP cases with members of the Rochester Epidemiology Project incident cohort who were objectively diagnosed with VIE 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, tolleting, transferring, bed positioning, or wheel-chair use; or to need physical therapy, rehabilitation, clinical monitoring, or wound care and were less likely to have neurologic disease. There were 53 MCMRP VIE cases vs 161 Rochester Epidemiology Project NH VIE cases; the proportion with pulmonary embolism was 21% vs 62%; 1-year mortality was 24% vs 55%. CONCLUSION: Administrative data from NHs reveal important VIE risk factors not routinely documented in hospital or ambulatory records. However, ascertainment of VIE 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 (23.5%) had positive results for one or both tests (13 [9.5%], LA-positive only; 76 [55.5%], 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]

Abstract: Deep vein thrombosis (DVT) and pulmonary embolism (PE), known collectively as venous thromboembolism (VTE), affect an estimated 900,000 people in the U.S. each year, resulting in several hundred thousand hospitalizations and about 300,000 deaths. Despite this substantial public health burden, no systematic collection of VTE-related morbidity and mortality data exists in the U.S. The available information about disease prevalence and incidence consists of estimates based mainly on population-based epidemiologic studies and analysis of hospital discharge or health insurance claims databases. The limited scope of the available data has raised the question of whether a systematic surveillance system for VTE should be established. To help answer this question and to make recommendations for the next steps toward better surveillance of VTE, the CDC asked the American Society of Hematology (ASH) to convene a national workshop of stakeholders representing relevant federal agencies, experts in VTE epidemiology and treatment, public health experts in VTE, and patient representatives. These groups were assembled by ASH for a 1-day meeting in Washington DC. The subspecialty experts included representatives from internal medicine, cardiovascular diseases, adult and pediatric hematology, surgery, obstetrics and gynecology, radiology, emergency medicine and trauma care, hospital practice and critical care, and geriatrics. Experts in epidemiology, healthcare quality, and health policy also participated. During the workshop, experts discussed their perspectives on the burden of disease from VTE and its diagnosis, treatment, and prevention. The workshop also focused on the advisability and feasibility of establishing systematic surveillance for VTE and included preliminary discussion of the advantages and disadvantages of various approaches. The workshop concluded that (1) improved utilization in clinical practice of existing, proven-effective preventive measures is critical to reducing the disease burden from VTE; (2) systematic surveillance of DVT and PE is needed to provide nationally representative data on the prevalence and annual incidence of DVT and PE in the U.S.; (3) tracking and documenting changes in the incidence of DVT and PE through systematic surveillance will be important to enhance prevention efforts; and (4) the CDC should convene a second group of experts to advise the agency in detail on the strengths, weaknesses, and feasibility of possible approaches to systematic surveillance for DVT and PE. [Copyright &y& Elsevier]