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Prepublished online as a Blood First Edition Paper on September 26, 2002; DOI 10.1182/blood-2002-05-1416.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Laboratory for Clinical Biochemistry Research
and Departments of Medicine, Pathology, and Biochemistry, University of
Vermont, Colchester; Division of Epidemiology, School of Public Health,
University of Minnesota, Minneapolis; Department of Internal Medicine,
University of Texas, Houston; Department of Epidemiology, University of
North Carolina, Chapel Hill; and Department of Epidemiology, University
of Washington, Seattle.
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.
(Blood. 2003;101:1243-1248) Our understanding of hemostatic disorders related
to venous thrombosis has increased significantly since the early 1990s
and the discovery of the factor V Leiden mutation.1
However, even though up to 35% of unselected patients with a first
thrombosis possess either factor V Leiden or the prothrombin 20210A
gene variant,2 approximately 40% of patients with venous
thrombosis in the presence of a positive family history do not have
identifiable hemostatic disorders.3 Therefore, further
study of hemostatic factors in relation to occurrence of venous
thrombosis is warranted.
Plasma levels of fibrin fragment D-dimer are elevated during acute
venous thrombosis because D-dimer is a marker of fibrin formation and
reactive fibrinolysis. In clinical settings, a low D-dimer
concentration may be useful for exclusion of acute
thrombosis.4 Among healthy individuals, there is
significant between-person variability of D-dimer concentration within
the normal range, and concentrations of plasma D-dimer in the top third
or fourth of the normal population distribution were associated with
increased risk of future myocardial infarction in several prospective
studies.5-9 In this context, D-dimer may represent the
summation of procoagulant balance or genetic factors, the extent of
subclinical atherosclerosis, or the presence of underlying coagulation
disorders that predispose to coronary thrombosis.10 Two
case-control studies reported that those with a history of deep vein
thrombosis were more likely than controls to have elevated D-dimer
concentration,11,12 and a third study reported a high
negative predictive value for recurrent venous thrombosis among those
with low D-dimer after initial treatment.13
The Longitudinal Investigation of Thromboembolism Etiology (LITE) is a
population-based prospective study of the incidence and risk factors
for venous thrombosis. We evaluated the association of baseline D-dimer
with incidence of venous thrombosis in this study.
Study population and baseline assessments
Nested case-control design
Controls were selected at random from the ARIC and CHS cohorts, with a ratio of 2.1 controls per case, and frequency matched to the cases by age (5-year groupings), sex, race (white, nonwhite), study (ARIC, CHS), and follow-up time (within 2 years).18 Selection yielded 390 ARIC controls and 298 CHS controls. Laboratory methods Stored plasma and DNA were retrieved for the selected cases and controls. If baseline plasma samples were limited, previously thawed, or exhausted for a participant a sample was retrieved from the next visit, approximately 3 years after baseline (n = 79 cases and 131 controls; 12 cases whose thrombosis was before the second visit). If neither sample was available or the D-dimer assay could not be performed, results were considered missing (n = 28 cases and 72 controls). The percentage of missing samples for D-dimer measurement did not differ significantly comparing cases to controls (P = .29). DNA was missing or permission to use it was not given for 6.2% of ARIC and 8.5% of CHS participants.D-dimer was measured at the University of Vermont with an enzyme-linked
immunosorbent assay (ELISA) using 2 monoclonal antibodies against
nonoverlapping determinants of D-dimer.19 The analytic coefficient of variation ranged from 7.5% to 10.2% from higher to
lower D-dimer concentrations. D-dimer by this method has longitudinal within-individual variability comparable to serum
cholesterol20 and is stable in long-term storage at
The factor V Leiden (1691G>A) mutation and prothrombin 20210A variant were detected using standard methods.2,22 Homozygosity for either trait was rare (3 with factor V Leiden, 0 with prothrombin variant) so heterozygotes and homozygotes were pooled for analysis. Factor VIII coagulant activity (factor VIII:c) was measured in all ARIC and CHS participants at baseline as previously reported.17,23 Statistical analyses The association of baseline D-dimer with other factors was analyzed in the control group using analysis of variance. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals (CIs) for venous thrombosis in relation to quintiles of the D-dimer distribution for combined case and control subjects. A test for trend in odds ratios was conducted using ordinal values for each quintile in logistic regression. Adjustment was made for factors previously associated venous thrombosis in the LITE study: age in all models, and race, sex, body mass index (BMI), factor V Leiden, prothrombin 20210A, and factor VIII:c in additional models. Analyses were repeated excluding the 12 cases whose D-dimer was measured after their thrombosis. Logistic regression analyses were repeated and stratified by study (ARIC and CHS) and by race (whites and nonwhites). Logistic regression analyses were also performed for prespecified subgroups (incident versus recurrent thrombosis, deep vein thrombosis versus pulmonary embolus, and idiopathic versus secondary thrombosis, with or without cancer) using all controls for comparison. Interactions of D-dimer with age, factor V Leiden, prothrombin 20210A variant, and elevated factor VIII:c were examined for idiopathic thrombosis by cross-classification.
D-dimer was measured in 923 subjects, 307 who had venous thrombosis during 8 years of follow-up and 616 who did not. Among the 923 subjects, the average baseline age was 64 years (range, 45-94 years), 53% were women, and 78% were white (most nonwhites were black). The distributions of these characteristics were similar between cases and controls due to the matching. BMI and factor VIII:c were higher among cases than controls (P < .001 for both). The mean BMI in cases and controls was 29.0 and 27.6 kg/m2, respectively. These values for factor VIII:c were 145% and 133%, respectively. Approximately 14% of cases and 4% of controls carried factor V Leiden, and 4% of cases and 2% of controls carried the prothrombin 20210A polymorphism. Both gene variants were rare among nonwhites (211 nonwhites, 2 with factor V Leiden, and 1 with prothrombin 20210A); therefore interaction analyses of the gene variants with D-dimer included whites only. Associations of D-dimer with several established risk factors for
venous thrombosis are shown in Table 1.
Higher D-dimer concentration was associated with older age, nonwhite
race, and higher factor VIII:c. The mean factor VIII:c was 144% in the
highest quintile of D-dimer compared to 123% in the lowest quintile.
Factor V Leiden and prothrombin 20210A were more common among those
with higher D-dimer. For 134 participants with factor V Leiden,
prothrombin 20210A, or factor VIII:c above the 80th percentile, the
geometric mean D-dimer concentration was 155.1 ng/mL compared to 111.6 ng/mL among 423 subjects without any of these factors
(P = .0002).
Figure 1 shows the distribution of
D-dimer values among cases and controls, demonstrating higher values in
cases. Overall, the risk of venous thrombosis increased substantially
with increasing baseline D-dimer concentration (Table
2). Nearly 30% of cases had D-dimer
values in the highest quintile of the distribution, whereas only 12%
had D-dimer in the lowest quintile. For D-dimer concentrations in the
third through fifth, compared to the first quintile, the age-adjusted
odds ratios for thrombosis were more than 2-fold increased, with a
fifth quintile odds ratio of 4.2 (95% CI, 2.6-6.8). Assessment of the
confounding effects of other factors on the association between D-dimer
and venous thrombosis is shown in Figure
2 and Table 2. Adjustment for age, sex,
race, and BMI slightly reduced the quintile-specific odds ratios.
Further adjustment for hemostatic risk factors (factor V Leiden,
prothrombin 20210A, and factor VIII:c) yielded a fifth compared to
first quintile odds ratio of 3.0 (95% CI, 1.7-5.2). With further
adjustment for factor VIII:c alone this odds ratio was 3.3 (95% CI,
2.0-5.5). Results did not differ materially with exclusion of 12 participants (4% of cases) whose thrombosis occurred before D-dimer
measurement, with exclusion of those with D-dimer above the 97.5 percentile, or with further adjustment for baseline C-reactive protein
or fibrinogen concentrations or smoking status.
The relationship of higher D-dimer to venous thrombosis was present among all subgroups analyzed in age-adjusted models in Table 2. The association of D-dimer with thrombosis was larger in women than in men, and in the older CHS participants than the younger ARIC participants, but the CIs overlapped widely. Similar findings were observed comparing incident to recurrent thrombosis: fifth quintile odds ratio 3.7 (95% CI, 2.2-6.2) for incident and 7.6 (95% CI, 2.4-24.1) for recurrent thrombosis. There were no differences in risk for elevated D-dimer comparing those with deep vein thrombosis to pulmonary embolus with or without a deep vein thrombosis. The association of D-dimer with thrombosis persisted throughout the duration of follow-up, but appeared larger for events occurring earlier during follow-up. For the 73 thrombosis events occurring within 2.5 years of phlebotomy, adjusting for age, race, sex, and BMI, the fifth quintile odds ratio was 7.5 (95% CI, 2.9-18.2), whereas for 222 later events the odds ratio was 3.1 (95% CI, 1.8-5.4). Figure 3 shows the association of
baseline D-dimer with incident venous thrombosis based on the presence
or absence of acquired risk factors for thrombosis. The relative risks
of idiopathic thrombosis and secondary thrombosis unrelated to cancer
were similar, with fifth versus first quintile age, sex, race, and
BMI-adjusted odds ratios of 5.5 (95% CI, 2.5-11.8) and 5.3 (95% CI,
2.1-13.3), respectively. Further adjustment for factor V Leiden,
prothrombin 20210A, and factor VIII:c yielded odds ratios of 3.5 (95%
CI, 1.5-8.3) and 4.8 (95% CI, 1.6-14.2), respectively. By contrast, there was no association of baseline D-dimer with the occurrence of
cancer-associated venous thrombosis, with a fifth quintile adjusted
odds ratio of 1.1 (95% CI, 0.5-2.7).
Considering only those 235 subjects with venous thrombosis that
was unrelated to cancer, in comparison to all controls, the joint
associations of D-dimer above the 60th percentile (159.3 ng/mL) with
other hemostatic risk factors for venous thrombosis are shown in Table
3. In the absence of elevated D-dimer,
the presence of factor V Leiden, prothrombin 20210A, or elevated factor VIII:c was associated with increased risk of venous thrombosis. In the
absence of a hemostatic defect, D-dimer above 159.3 ng/mL was
associated with a 2-fold increased risk of thrombosis. The combination
of factor V Leiden, prothrombin 20210A, or elevated factor VIII:c with
elevated D-dimer conveyed lower odds ratios of venous thrombosis than
expected by an additive model of individual risk factors. If higher
values of D-dimer (80th or 90th percentile) were chosen to define
elevated D-dimer, or if participants with isolated pulmonary embolus
were excluded,24 inferences from this analysis were
similar.
The main finding of this study was a graded increase in the future occurrence of venous thrombosis with increasing baseline concentration of D-dimer in a sample of the general US population. The association was independent of several common thrombosis risk factors, including factor V Leiden, the prothrombin 20210A variant, and factor VIII:c. Adjusting for demographic factors and BMI, the risk of venous thrombosis for the highest versus lowest 20% of D-dimer values was 3.9-fold increased, and adjusting further for hemostatic factors, the risk was 3.0-fold increased. These odds ratios were even higher when those with cancer-associated thrombosis were excluded. The association of D-dimer with venous thrombosis was observed consistently in subgroups defined by age, race, thrombosis type, time between phlebotomy and thrombosis, and by whether the thrombosis was a first or recurrent event or was idiopathic or associated with acquired risk factors other than cancer. There was no association of D-dimer with occurrence of cancer-associated venous thrombosis. A case-control study including 66 women, aged 45 to 64, with deep vein thrombosis, reported an association between higher D-dimer concentration and a history of thrombosis.12 Similarly, in another report, 474 patients with a prior history of deep vein thrombosis were more likely than 474 controls to have elevated D-dimer concentration.11 In both studies, the odds ratios for thrombosis were similar to those observed here and were also present among those without known hemostatic defects. Our prospective data add important new information because D-dimer increases more than 100-fold during acute thrombosis, and it is unknown whether D-dimer returns to an individual's long-term normal value over time after a thrombotic event. Our findings differ from the only other prospective study of D-dimer and the risk of venous thrombosis, which assessed the occurrence of deep vein thrombosis after elective hip replacement among 375 patients.25 In that study, mean preoperative D-dimer concentration was higher among 120 patients who subsequently developed postoperative deep vein thrombosis than those who did not, but this difference was not independent of other factors.25 There are a few possible pathophysiologic explanations for an association of D-dimer with venous thrombosis. It is unlikely that D-dimer itself is a causal factor in venous thrombosis. We hypothesize that it is a marker for other factors related to the pathophysiology of thrombosis. First, considering that venous thrombosis is an oligogenic disease,1 elevated D-dimer may reflect currently unknown hemostatic disorders that are associated with venous thrombosis. Indeed, D-dimer was higher in the presence of factor V Leiden, prothrombin 20210A, or elevated factor VIII:c, all recognized as common risk factors for thrombosis. However, it remained associated with thrombosis, independent of these factors. Other risk factors for thrombosis, including deficiencies of protein C, protein S, or antithrombin are probably too rare in the general population (< 1% each)1 to be considered responsible for the association of D-dimer with thrombosis. A recent finding that D-dimer has high heritability supports the notion that D-dimer reflects genetic factors.26 These might relate to regulatory proteins for coagulation factor production or clearance in general or to differences in coagulation factors themselves. Second, D-dimer might reflect other environmental risk factors for thrombosis. Higher D-dimer concentration is associated with smoking status27 and some coagulation and inflammation markers such as fibrinogen and C-reactive protein.7 However, none of these factors were associated with the risk of venous thrombosis in the LITE population, and none were confounders of the D-dimer association with venous thromboembolism.28 Third, because fibrinolytic factors, such as plasminogen activator inhibitor-1 and tissue plasminogen activator, are not generally considered risk factors for venous thrombosis,29,30 it is likely that higher D-dimer reflects increased fibrin formation rather than fibrinolytic reactivity. Our findings and those of others5-9,11-13 would support further study of phenotypic and genotypic determinants of fibrin formation. Higher D-dimer is correlated with more advanced cancer stage.31,32 Even though D-dimer was not associated with cancer-associated thrombosis in this study, at the time of phlebotomy most participants did not have a history of cancer, and among CHS participants none were receiving active treatment for cancer. Therefore, further study of D-dimer as a risk factor for venous thrombosis among patients with active cancer may be useful. A few points should be considered in interpreting these findings. First, D-dimer was measured using a research-based ELISA. To our knowledge, in nonacute clinical settings, this assay has not been compared to commercially available assays, and this would be necessary prior to considering use of D-dimer for thrombosis risk assessment. Second, inclusion as a case of venous thrombosis in this study required a clinical diagnosis of thrombosis, so some fatal pulmonary emboli and asymptomatic thromboses were under ascertained. Because venous thrombosis is a relatively rare disease, misclassification based on this or other factors, would not be expected to change the results significantly, and would lead to underestimation of the true risk associated with D-dimer. In conclusion, higher D-dimer concentration was associated with increased risk of subsequent venous thrombosis in a general US population. Assessment of D-dimer may provide different clinical information than assessment of other thrombosis risk factors, such as factor V Leiden or obesity. Based on these data, calculation of the attributable risk fraction of venous thrombosis associated with D-dimer suggests that 13.3% of events may be accounted for by D-dimer in the highest quintile. The strength of the association observed here, and its consistency in various subgroups, suggests potential clinical roles for D-dimer assessment that could be tested in future clinical studies. These studies should include assessment of D-dimer with more readily available assay systems than the research-based ELISA used here. In addition, based on this and other recent findings,11,12,26 further study of genetic determinants of elevated D-dimer in healthy populations is indicated.
We are grateful to ARIC and CHS investigators and the study participants for their many years of important contributions to these studies. We also thank Ms Cathy Tilley and Ms Elaine Cornell for technical support of this study.
Submitted May 15, 2002; accepted September 17, 2002.
Prepublished online as Blood First Edition Paper, September 26, 2002; DOI 10.1182/blood-2002-05-1416.
Supported by the Atherosclerosis Risk in Communities Study, funded by contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, and the Cardiovascular Health Study, funded by contracts N01-HC-85079 to N01-HC-85086 from the National Heart, Lung, and Blood Institute. The Longitudinal Investigation of Thromboembolism Etiology was funded by R01 HL59367 from the National Heart, Lung, and Blood Institute.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Mary Cushman, Departments of Medicine and Pathology, 208 S Park Dr, Suite 2, Colchester, VT 05446; e-mail: mary.cushman{at}uvm.edu.
1. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet. 1999;353:1167-1173[CrossRef][Medline] [Order article via Infotrieve].
2.
Poort SR, Rosendaal FR, Reitsma PH, Bertina RM.
A common genetic variant in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.
Blood.
1996;88:3698-3703 3. Lane D, Mannucci P, Bauer K, et al. Inherited thrombophilia: part 1. Thromb Haemost. 1996;76:651-662[Medline] [Order article via Infotrieve]. 4. Perrier A, Desmarais S, Miron MJ, et al. Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet. 1999;353:190-195[CrossRef][Medline] [Order article via Infotrieve].
5.
Ridker PM, Hennekens CH, Cerskus A, Stampfer MJ.
Plasma concentration of cross-linked fibrin degradation product (D-dimer) and the risk of future myocardial infarction among apparently healthy men.
Circulation.
1994;90:2236-2240 6. Lowe GDO, Yarnell JWG, Sweetnam PM, et al. Fibrin D-dimer, tissue plasminogen activator, plasminogen activator inhibitor, and the risk of major ischemic heart disease in the Caerphilly Study. Thromb Haemost. 1998;79:129-133[Medline] [Order article via Infotrieve].
7.
Cushman M, Lemaitre RN, Kuller LH, et al.
Fibrinolytic activation markers predict myocardial infarction in the elderly: the Cardiovascular Health Study.
Arterioscler Thromb Vasc Biol.
1999;19:493-498
8.
Danesh J, Whincup P, Walker M, et al.
Fibrin D-dimer and coronary heart disease: prospective study and meta-analysis.
Circulation.
2001;103:2323-2327
9.
Folsom AR, Aleksic N, Park E, et al.
A prospective study of fibrinolytic factors and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study.
Arterioscler Thromb Vasc Biol.
2001;21:611-617 10. Cushman M. Hemostatic risk factors for cardiovascular disease. In: Schechter GP,Hoffman R,Schrier SL, eds. Hematology 1999. Washington, DC: The American Society of Hematology; 1999:236-242. 11. Andreescu ACM, Cushman M, Rosendaal FR. D-dimer as a risk factor for deep vein thrombosis: the Leiden Thrombophilia Study. Thromb Haemost. 2002;87:47-51[Medline] [Order article via Infotrieve]. 12. Lowe G, Woodward M, Vessey M, et al. Thrombotic variables and risk of idiopathic venous thromboembolism in women aged 45-64 years: relationships to hormone replacement therapy. Thromb Haemost. 2000;83:530-535[Medline] [Order article via Infotrieve]. 13. Palareti G, Legnani C, Cosmi B, et al. Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost. 2002;87:7-12[Medline] [Order article via Infotrieve].
14.
The ARIC Investigators.
The Atherosclerosis Risks in Communities (ARIC) study: design and objectives.
Am J Epidemiol.
1989;129:687-702 15. Fried LP, Borhani NO, Enright P, et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol. 1991;1:263-276[Medline] [Order article via Infotrieve]. 16. Papp A, Hatzakis H, Bracey A, Wu K. ARIC hemostasis study-I. Development of a blood collection and processing system suitable for multicenter hemostatic studies. Thromb Haemost. 1989;61:15-19[Medline] [Order article via Infotrieve]. 17. Cushman M, Cornell ES, Howard PR, Bovill EG, Tracy RP. Laboratory methods and quality assurance in the Cardiovascular Health Study. Clin Chem. 1995;42:264-270. 18. Rothman KJ, Greenland S. Modern Epidemiology. Philadelphia, PA: Lippincott-Raven; 1998. 19. Declerck PJ, Mombaerts P, Holvoet P, De Mol M, Collen D. Fibrinolytic response and fibrin fragment D-dimer levels in patients with deep vein thrombosis. Thromb Haemost. 1987;58:1024-1029[Medline] [Order article via Infotrieve].
20.
Sakkinen PA, Macy EM, Callas PW, et al.
Analytical and biologic variability in measures of hemostasis, fibrinolysis, and inflammation: assessment and implications for epidemiology.
Am J Epidemiol.
1999;149:261-267 21. Lewis MR, Callas PW, Jenny NS, Tracy RP. Longitudinal stability of coagulation, fibrinolysis, and inflammation factors in stored plasma samples. Thromb Haemost. 2001;86:1495-1500[Medline] [Order article via Infotrieve]. 22. Bertina RM, Koeleman BP, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369:64-67[CrossRef][Medline] [Order article via Infotrieve]. 23. Sharrett A, and the ARIC Investigators. The Atherosclerosis Risk in Communities study: introduction and objectives of the hemostasis component. Ann Epidemiol. 1992;2:467-469[Medline] [Order article via Infotrieve].
24.
Perrier A.
Deep vein thrombosis and pulmonary embolism: a single disease entity with different risk factors?
Chest.
2000;118:1234-1236 25. Lowe GD, Haverkate F, Thompson SG, et al. Prediction of deep vein thrombosis after elective hip replacement surgery by preoperative clinical and haemostatic variables: the ECAT DVT study. European Concerted Action on Thrombosis. Thromb Haemost. 1999;81:879-886[Medline] [Order article via Infotrieve]. 26. Ariëns RA, de Lange M, Snieder H, et al. Activation markers of coagulation and fibrinolysis in twins: heritability of the prethrombotic state. Lancet. 2002;359:667-671[CrossRef][Medline] [Order article via Infotrieve].
27.
Lee AJ, Fowkes GR, Lowe GD, Rumley A.
Determinants of fibrin D-dimer in the Edinburgh Artery Study.
Arterioscler Thromb Vasc Biol.
1995;15:1094-1097
28.
Tsai AW, Folsom AR, Cushman M, et al.
Cardiovascular risk factors and venous thromboembolism incidence: the Longitudinal Investigation of Thromboembolism Etiology (LITE) study.
Arch Intern Med.
2002;162:1182-1189
29.
Prins M, Hirsh J.
A critical review of the evidence supporting a relationship between impaired fibrinolytic activity and venous thromboembolism.
Arch Intern Med.
1991;151:1721-1731 30. Crowther MA, Roberts J, Roberts R, et al. Fibrinolytic variables in patients with recurrent venous thrombosis: a prospective cohort study. Thromb Haemost. 2001;85:390-394[Medline] [Order article via Infotrieve]. 31. Edwards CM, Warren J, Armstrong L, Donnelly PK. D-dimer: a useful marker of disease stage in surgery for colorectal cancer. Br J Surg. 1993;80:1404-1405[Medline] [Order article via Infotrieve].
32.
Blackwell K, Haroon Z, Broadwater G, et al.
Plasma D-dimer levels in operable breast cancer patients correlate with clinical stage and axillary lymph node status.
J Clin Oncol.
2000;18:600-608
© 2003 by The American Society of Hematology.
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 |
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 I. Pabinger and C. Ay Biomarkers and Venous Thromboembolism Arterioscler. Thromb. Vasc. Biol., March 1, 2009; 29(3): 332 - 336. [Abstract] [Full Text] [PDF]
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|
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|
 |
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|
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|
|
|
|
|
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 U. Nowak-Gottl and A. Kosch Factor VIII, D-Dimer, and Thromboembolism in Children N. Engl. J. Med., September 9, 2004; 351(11): 1051 - 1053. [Full Text] [PDF]
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M. Sivakumaran, N. Malton, and M. Cushman Plasma D-dimer measurement as a predictor of venous thrombosis Blood, December 15, 2003; 102(13): 4618 - 4619. [Full Text] [PDF]
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 S. Eichinger, E. Minar, C. Bialonczyk, M. Hirschl, P. Quehenberger, B. Schneider, A. Weltermann, O. Wagner, and P. A. Kyrle D-Dimer Levels and Risk of Recurrent Venous Thromboembolism JAMA, August 27, 2003; 290(8): 1071 - 1074. [Abstract] [Full Text] [PDF]
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| Copyright © 2003 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
70°C.
represent
age-adjusted models; 
, models adjusted for age, sex, race, and BMI;
, models adjusted for all previous factors and factor V Leiden,
prothrombin 20210A, and factor VIII:c above the 80th percentile.
D-dimer quintile definitions are given in Table 