@article {716, title = {Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE).}, journal = {Am J Med}, volume = {113}, year = {2002}, month = {2002 Dec 01}, pages = {636-42}, abstract = {

PURPOSE: We sought to assess prospectively whether higher levels of blood coagulation factors and inflammation markers are risk factors for venous thromboembolism.

SUBJECTS AND METHODS: In two pooled population-based cohort studies, we measured levels of factor VII, factor VIII, von Willebrand factor, fibrinogen, and C-reactive protein, and white blood cell count, in samples obtained from 19,237 adults with no baseline history of venous thromboembolism, cancer, or warfarin use. The endpoint was validated venous thromboembolism during follow-up (median, 7.8 years).

RESULTS: A total of 159 venous thromboembolism events occurred. Factor VIII and von Willebrand factor were linearly associated with increased risk of venous thromboembolism (P for trend <0.0001). As compared with those in the lowest quartile, the multivariate-adjusted hazard ratio (HR) of venous thromboembolism was 2.6 (95\% confidence interval [CI]: 1.6 to 4.3) for factor VIII levels in the highest quartile and 3.8 (95\% CI: 2.0 to 7.2) for the highest fifth percentile. For von Willebrand factor, the hazard ratios in middle-aged subjects were 4.6 (95\% CI: 2.2 to 9.2) for the highest quartile and 7.6 (95\% CI: 3.1 to 18) for the highest fifth percentile. Factor VII levels above the 95th percentile, as compared with the lowest quartile, also conveyed a higher risk of venous thromboembolism (HR = 2.4; 95\% CI: 1.2 to 4.8). In contrast, there was no association of venous thromboembolism with fibrinogen or C-reactive protein levels, or white cell count.

CONCLUSIONS: In this prospective study, elevated factor VIII and von Willebrand factor levels were common, independent, and dose-dependent risk factors for venous thromboembolism, and an elevated factor VII level was a possible risk factor. Venous thromboembolism, unlike arterial disease, was not related to inflammatory markers.

}, keywords = {Aged, Biomarkers, Blood Coagulation Factors, C-Reactive Protein, Cohort Studies, Confidence Intervals, Factor VII, Female, Fibrinogen, Humans, Inflammation Mediators, Longitudinal Studies, Male, Middle Aged, Multivariate Analysis, Prospective Studies, Risk Assessment, Risk Factors, Sensitivity and Specificity, Thromboembolism, Venous Thrombosis, von Willebrand Factor}, issn = {0002-9343}, doi = {10.1016/s0002-9343(02)01345-1}, author = {Tsai, Albert W and Cushman, Mary and Rosamond, Wayne D and Heckbert, Susan R and Tracy, Russell P and Aleksic, Nena and Folsom, Aaron R} } @article {684, title = {A prospective study of venous thromboembolism in relation to factor V Leiden and related factors.}, journal = {Blood}, volume = {99}, year = {2002}, month = {2002 Apr 15}, pages = {2720-5}, abstract = {

The aim of this study was to examine the occurrence of venous thromboembolism (VTE) in relation to factor V-related risk factors. Using a nested case-control design combining 2 population-based prospective studies, we measured factor V Leiden, HR2 haplotype, activated protein C (APC) resistance, and plasma factor V antigen in 335 participants who developed VTE during 8 years of follow-up and 688 controls. The overall odds ratio (OR) of VTE was 3.67 (95\% CI, 2.20-6.12) in participants carrying factor V Leiden compared with noncarriers. APC resistance measured after predilution with factor V-deficient plasma conferred an OR of 2.58 (95\% CI, 1.62-4.10). All 3 participants homozygous for the HR2 haplotype had a VTE, and the OR of VTE for homozygosity was estimated to be 5.5 (95\% CI, 2.45-12.5). Carriers of the HR2 haplotype otherwise were not at increased risk of VTE overall (OR = 1.05; 95\% CI, 0.64-1.72), but double heterozygotes for HR2 and factor V Leiden carried an OR of idiopathic VTE of 16.3 (95\% CI, 1.7-159) compared with noncarriers. Factor V antigen also was not associated with VTE overall, but for participants with the combination of high factor V antigen plus factor V Leiden the OR of idiopathic VTE was 11.5 (95\% CI, 4.2-31.4). In the general population, APC resistance and factor V Leiden were important VTE risk factors; homozygosity for the HR2 haplotype may be a risk factor but was rare; otherwise, HR2 haplotype and factor V antigen were not risk factors except in carriers of factor V Leiden.

}, keywords = {Activated Protein C Resistance, Aged, Cohort Studies, Continental Population Groups, Factor V, Genotype, Haplotypes, Humans, Incidence, Longitudinal Studies, Middle Aged, Odds Ratio, Prospective Studies, Risk Factors, Thromboembolism, Venous Thrombosis}, issn = {0006-4971}, doi = {10.1182/blood.v99.8.2720}, author = {Folsom, Aaron R and Cushman, Mary and Tsai, Michael Y and Aleksic, Nena and Heckbert, Susan R and Boland, Lori L and Tsai, Albert W and Yanez, N David and Rosamond, Wayne D} } @article {693, title = {Protein C, antithrombin, and venous thromboembolism incidence: a prospective population-based study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {22}, year = {2002}, month = {2002 Jun 01}, pages = {1018-22}, abstract = {

Although deficiencies of protein C and antithrombin, 2 natural plasma anticoagulants, are known risk factors for venous thrombosis, population-based prospective incidence data on these associations are lacking. Venous thromboembolic events have been identified in adults in 2 longitudinal cohort studies, the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS). Incidence was examined in relation to prediagnostic plasma levels of protein C (ARIC Study only) and antithrombin. Over a mean of 8.1 years of follow-up, there were 130 incident venous thromboembolic events that were not due to cancer in the ARIC Study. The age-adjusted incidence was elevated 3.36-fold (95\% CI 1.24 to 9.11) in the 1.1\% of subjects with protein C values <2.0 mg/L compared with subjects with higher values. In contrast, in the ARIC Study and the CHS, there was no association between low plasma antithrombin and venous thromboembolism. In conclusion, in this population-based study, a low protein C, but not antithrombin, level has been determined to be associated with an increased incidence of venous thromboembolism. Attributable risk estimates suggest that low protein C levels account for approximately 2.5\% of venous thromboembolic events in the ARIC population.

}, keywords = {Adult, Aged, Aged, 80 and over, Antithrombins, Arteriosclerosis, Cohort Studies, Humans, Incidence, Longitudinal Studies, Middle Aged, Odds Ratio, Population Surveillance, Prospective Studies, Protein C, Protein C Deficiency, Pulmonary Embolism, Thromboembolism, Venous Thrombosis}, issn = {1524-4636}, doi = {10.1161/01.atv.0000017470.08363.ab}, author = {Folsom, Aaron R and Aleksic, Nena and Wang, Lu and Cushman, Mary and Wu, Kenneth K and White, Richard H} } @article {706, title = {Fibrin fragment D-dimer and the risk of future venous thrombosis.}, journal = {Blood}, volume = {101}, year = {2003}, month = {2003 Feb 15}, pages = {1243-8}, abstract = {

Plasma D-dimer concentration rises more than 100-fold during acute deep vein thrombosis, but there are no prospective data concerning D-dimer as a risk factor for incident venous thrombosis in a general population. Incident venous thrombosis was ascertained in 2 prospective observational studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Of 21 690 participants enrolled between 1987 and 1993, after 8 years of follow-up, D-dimer was measured using baseline stored plasma of 307 participants who developed venous thrombosis and 616 who did not. Relative to the first quintile of the distribution of D-dimer, the age-adjusted odds ratios for future venous thrombosis for the second to fifth quintiles of D-dimer were 1.6, 2.3, 2.3, and 4.2, respectively (P for trend <.0001). Following added adjustment for sex, race, body mass index, factor V Leiden, prothrombin 20210A, and elevated factor VIII coagulant activity (factor VIII:c), these odds ratios were 1.5, 2.1, 1.9, and 3.0, respectively (P for trend <.0001). Among those with idiopathic thrombosis or secondary thrombosis unrelated to cancer, the adjusted fifth quintile odds ratios were 3.5 and 4.8, respectively. By contrast, D-dimer in the fifth versus first quintile was not related to occurrence of cancer-associated thrombosis (odds ratio, 1.1). Odds ratios for elevated D-dimer were consistently elevated in subgroups defined by age, sex, race, duration of follow-up, and thrombosis type (deep vein thrombosis or pulmonary embolus). D-dimer is strongly and positively related to the occurrence of future venous thrombosis.

}, keywords = {Aged, Body Mass Index, Cohort Studies, Continental Population Groups, Factor V, Factor VIII, Female, Fibrin Fibrinogen Degradation Products, Humans, Longitudinal Studies, Male, Middle Aged, Odds Ratio, Prospective Studies, Prothrombin, Risk Factors, Venous Thrombosis}, issn = {0006-4971}, doi = {10.1182/blood-2002-05-1416}, author = {Cushman, Mary and Folsom, Aaron R and Wang, Lu and Aleksic, Nena and Rosamond, Wayne D and Tracy, Russell P and Heckbert, Susan R} } @article {726, title = {Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE).}, journal = {Am J Hematol}, volume = {72}, year = {2003}, month = {2003 Mar}, pages = {192-200}, abstract = {

We sought to examine prospectively the association of serum homocysteine and the methylene tetrahydrofolate reductase (MTHFR) C677T gene polymorphism with risk of venous thromboembolism (VTE). We studied these relationships in a nested case-control study of 303 VTE cases and 635 matched controls from a population-based cohort of 21,680 adults from six U.S. communities. The highest quintile of serum homocysteine carried a non-statistically significant adjusted odds ratio of 1.55 (95\% CI, 0.93-2.58) compared to the lowest quintile in the overall cohort but a significant association among adults aged 45-64 years (OR = 2.05, 95\% CI, 1.10-3.83) and an inverse association in those > or = 65 years of age. Carriers of the MTHFR C677T polymorphism were not at higher risk for VTE than those with normal genotype (OR = 0.74, 95\% CI = 0.56-0.98). Our prospective data showed, at most, a weak relationship between homocysteine and VTE risk, with associations larger among younger participants. MTHFR C677T was not a risk factor for VTE.

}, keywords = {Aged, Aging, Animals, Case-Control Studies, Cohort Studies, Factor V, Female, Genotype, Homocysteine, Humans, Longitudinal Studies, Male, Methylenetetrahydrofolate Reductase (NADPH2), Middle Aged, Odds Ratio, Oxidoreductases Acting on CH-NH Group Donors, Polymorphism, Genetic, Prospective Studies, Risk Factors, Venous Thrombosis}, issn = {0361-8609}, doi = {10.1002/ajh.10287}, author = {Tsai, Albert W and Cushman, Mary and Tsai, Michael Y and Heckbert, Susan R and Rosamond, Wayne D and Aleksic, Nena and Yanez, N David and Psaty, Bruce M and Folsom, Aaron R} }