This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Feinberg, W. M. Articles by Bovill, E. G. Search for Related Content PubMed PubMed Citation Articles by Feinberg, W. M. Articles by Bovill, E. G.

(Stroke. 1997;28:1101-1106.)
© 1997 American Heart Association, Inc.

Articles

Relationship Between Prothrombin Activation Fragment F1.2 and International Normalized Ratio in Patients With Atrial Fibrillation

William M. Feinberg, MD; Elaine S. Cornell, BA; Sarah D. Nightingale, BS; Lesly A. Pearce, MS; Russell P. Tracy, PhD; Robert G. Hart, MD; Edwin G. Bovill, MD; for the Stroke Prevention in Atrial Fibrillation Investigators

From the Department of Neurology, University of Arizona Health Sciences Center, Tucson (W.M.F.); Laboratory for Clinical Biochemistry Research, Department of Pathology, University of Vermont, Burlington (E.S.C., S.D.N., R.P.T., E.G.B.); Statistics and Epidemiology Research Corporation, Seattle, Wash (L.A.P.); and Department of Medicine (Neurology), University of Texas, San Antonio (R.G.H.).

Correspondence to Edwin G. Bovill, MD, Laboratory for Clinical Biochemistry Research, Department of Pathology, University of Vermont, 55A S Park Dr, Colchester, VT 05446. E-mail ebovill{at}moose.uvm.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose The prothrombin time (expressed as the international normalized ratio [INR]) is the standard method of monitoring warfarin therapy in patients with atrial fibrillation. Prothrombin activation fragment F1.2 provides an index of in vivo thrombin generation and might provide a better index of the effective intensity of anticoagulation. We examined the relationship between F1.2 and INR in patients with atrial fibrillation.

Methods We measured INR and F1.2 levels in 846 patients with atrial fibrillation participating in the Stroke Prevention in Atrial Fibrillation III study. Two hundred nineteen (26%) were taking aspirin alone, 326 (39%) were taking adjusted-dose warfarin, and 301 (36%) were taking a low fixed dose of warfarin (1 to 3 mg) plus aspirin (combination therapy). F1.2 levels were measured with an enzyme-linked immunosorbent assay.

Results Patients receiving adjusted-dose warfarin or combination therapy had significantly higher INR and significantly lower F1.2 values than those on aspirin alone (P.0001 for each of the four comparisons). F1.2 values (nanomolar) were inversely correlated with INR (F1.2=-0.1+2.3[1/INR]; R²=.37; P<.0001; simple linear regression). However, significant variability remained. Among patients receiving warfarin, older patients had higher F1.2 values than younger patients after adjustment for INR intensity (P<.001) in the model. There was no difference in the relationship between F1.2 and INR between men and women.

Conclusions Increasing intensity of anticoagulation, as measured by the INR, is associated with decreasing thrombin generation as measured by the F1.2 level, but significant variability exists in this relationship. Older anticoagulated patients have higher F1.2 values than younger patients at equivalent INR values. The clinical significance of these differences is not clear. F1.2 measurement might provide information regarding anticoagulation intensity in addition to that reflected by the INR.

Key Words: anticoagulants • atrial fibrillation • international normalized ratio • thrombin

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The prothrombin time is the standard method of monitoring oral anticoagulation therapy. The prothrombin time reflects in vitro clot generation in response to a standard amount of thromboplastin. The prothrombin time is now commonly reported as the INR.¹ The INR adjusts for differences between assays that use thromboplastins of differing sensitivities.^{2 3 4} However, even when the INR is used, differences occur among assays.^{5 6}

The prothrombin activation fragment F1-2 (F1.2) is an index of in vivo thrombin generation; one molecule of F1.2 is released with the generation of each thrombin molecule.^{7 8 9 10} F1.2 is markedly elevated in acute thrombotic conditions such as myocardial infarction.^{11 12} Anticoagulation suppresses the F1.2 level in a dose-response fashion,^{13 14 15} and even low- or "mini"-dose anticoagulation has been shown to affect F1.2 levels.^{16 17} Since the F1.2 level reflects thrombin activity more directly, it might be a better clinical marker of the intensity of anticoagulation.

The SPAF III study compares aspirin, warfarin, or aspirin plus a low fixed dose of warfarin in patients with atrial fibrillation for prevention of thromboembolism.^{18 19} To further study the relationship between F1.2 and INR, we examined these tests in SPAF study patients.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
SPAF Study Design
All patients were participants in the SPAF III trial performed at 20 clinical centers in the United States and Canada. The design of this study has been described in detail.¹⁸ Patients entering the SPAF trial were stratified as high or low risk for ischemic stroke and systemic embolism based on clinical characteristics derived from the SPAF I and II trials.^{19 20 21} Patients with a previous stroke or transient ischemic attack, systolic hypertension (>160 mm Hg) at study entry, poor left ventricular function (recent congestive heart failure or left ventricular shortening fraction 25% on echocardiogram), and women aged >75 years were deemed high risk. Patients with none of these characteristics were termed low risk.

Low-risk patients were treated with aspirin 325 mg/d. High-risk patients were randomly allocated to receive standard adjusted-dose warfarin anticoagulation (INR, 2.0 to 3.0) or aspirin (325 mg/d) plus a low fixed dose of warfarin (combination therapy). The fixed dose of warfarin was the lowest dose that prolonged the INR >1.2 but not >3 mg/d. The high-risk portion of the SPAF III trial was terminated earlier than expected because patients receiving combination therapy had a significantly higher rate of stroke and systemic emboli than those receiving adjusted-dose warfarin.¹⁹ The aspirin cohort study involving low-risk patients continues. The study was approved by the institutional review committee at each participating institution. All subjects gave informed consent.

This study of hemostatic markers represents a convenience sample of patients in the SPAF study. The SPAF Study Research Coordinators were asked to obtain blood for hemostatic markers at the 3-month study visit, the 1-year study visit, and then annually. We used the 3-month sample when done; otherwise we used the first sample available. Only one sample per patient was included in this study. We eliminated samples if a patient reported being off assigned therapy within the prior 2 weeks.

Blood Collection and Analysis
Blood collection tubes for F1.2 measurement were prepared at the Laboratory for Clinical Biochemistry Research, Department of Pathology, University of Vermont, and provided to each of the centers. Research personnel participating in blood collection received venipuncture training at the beginning of the SPAF III study. Data were collected regarding venipuncture quality, including number of needle punctures required, vein collapse, hematoma formation, leakage at site, tourniquet time, total venipuncture time, and venipuncture difficulty. Blood was collected with minimal stasis with a 21-gauge butterfly needle. Blood was drawn into a special coagulation tube designed to avoid in vitro coagulation activation. This tube, at final concentrations, contained 4.5 mmol/L EDTA, 200 KIU/mL aprotinin, and 25 µmol/L d-Phe-Pro-Arg chloromethyl ketone (a potent serine protease inhibitor).²² Blood for central determination of INR was collected into a 4.5-mL stoppered, silicon-coated glass tube containing 0.5 mL of 3.8% citrate. The evacuated tubes were mixed by gentle inversion for 30 seconds, and the "special" tube was placed on ice. The citrate tube was kept at room temperature.

Samples for central analysis were processed within 1 hour of phlebotomy. Tubes were centrifuged at 4°C for 30 000g·minutes. Plasma was aliquoted into color-coded 0.5-mL cryovials (USA Scientific) and frozen at -70° until shipment. Samples were shipped on dry ice via an overnight carrier.

F1.2 was measured with an enzyme-linked immunosorbent assay (Behring Inc). The interassay CV was 8%. Prothrombin times were primarily measured locally (70%) with a variety of thromboplastins. Local determination of INR was performed according to procedures of each local site. In a subgroup of patients in whom a local INR measurement was not available on the day of F1.2 measurement (n=273), a prothrombin time was measured in a citrated sample at the Laboratory for Clinical Biochemistry Research with the use of Innovin thromboplastin (Dade, Inc; international sensitivity index=0.97) on an MLA 700 Fibrinometer. FPA levels were measured on fibrinogen-free plasma by a double-antibody competition radioimmunoassay (Byk-Sangtec Diagnostica). Fibrinogen was extracted with bentonite.²³ The post–fibrinogen extraction CV was 12.4%; the total CV for the assay, including extraction, was 36.3%.

Statistical Analysis
Clinical characteristics were compared between patient groups with the use of Student's two-tailed t test or a ² analysis, as appropriate. INR values and F1.2 levels were compared between groups with a Wilcoxon rank sum test. The relationship among F1.2 values and INR values, both with and without adjustments for covariates, was evaluated with a linear regression model, complete with residual analysis and analysis for interaction terms. Statistical significance was accepted at the .05 level, and all tests were two-sided.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We measured INR and F1.2 in 908 study participants. Sixty samples (6.6%) were excluded because of unsatisfactory venipuncture (difficult venipuncture, multiple needle puncture, vein collapse, hematoma formation, leakage at site, tourniquet time >2 minutes). Two samples were further excluded from all analyses because of extremely elevated F1.2 values (F1.2=15.6 and 12.5 nmol/L, both values >10 SD above the mean). At the time of sample collection, 219 patients (26%) were taking aspirin, 326 (39%) were taking adjusted-dose warfarin, and 301 (36%) were taking low-dose warfarin plus aspirin (combination therapy). The mean age, sex, INR values, and F1.2 values in each therapy group are shown in Table 1. Patients receiving warfarin (either adjusted-dose warfarin or combination therapy, n=627) were older (71 versus 68 years; P<.001) and more often female (35% versus 17%; P<.0001) than those taking aspirin alone (Table 1). This was expected from the study design, since all women aged >75 years were considered high risk and were not eligible to receive aspirin alone.¹⁸ There was no difference in patient characteristics between those receiving adjusted-dose warfarin and those receiving combination therapy. Patients taking combination therapy and adjusted-dose warfarin had significantly lower F1.2 levels than those taking aspirin alone (Table 1).

View this table: [in this window] [in a new window]   Table 1. INR and F1.2 Levels According to Antithrombotic Therapy (n=846)

Levels of F1.2 were not related to INRs in patients receiving aspirin alone (R²=.001; P=.65). In patients receiving warfarin, F1.2 values were inversely related to INR values (R²=.37; P<.0001) (Figs 1 and 2). Patients receiving warfarin whose INR was <1.2 (n=118) did not have significantly different F1.2 values from those on aspirin alone (n=219; P=.37). The proportion of patients with an F1.2 value <1.4 nmol/L (the mean F1.2 value for patients receiving warfarin) increased from 12% and 15%, respectively, in those receiving aspirin and those receiving warfarin whose INR was <1.2 to 96% of those with an INR >3.0 (Table 2). Seventy-seven percent of those with an INR 2.0 had F1.2 values <1.0 nmol/L.

View larger version (14K): [in this window] [in a new window]   Figure 1. F1.2 levels versus INR in patients with atrial fibrillation receiving warfarin (n=627). F1.2 levels were inversely correlated with INR values, with the relationship F1.2=-0.1+2.3(1/INR).

View larger version (23K): [in this window] [in a new window]   Figure 2. F1.2 levels according to patient age and INR range. Shaded boxes represent data for patients aged 75 years and unshaded boxes for those aged >75 years. Central lines represent medians, and upper and lower edges of the solid boxes represent the 25th to 75th percentiles. Lines (whiskers) are drawn to the lowest and highest values within 1.5 box lengths from the edges of the box. Any values lying beyond these lines are plotted individually.

View this table: [in this window] [in a new window]   Table 2. Mean and Median F1.2 Levels for Patients on Aspirin Only and Within Each INR Range for Patients on Warfarin and Number of Patients Within Each INR Group With F1.2 <1.4 and <1.0 nmol/L

Increased age was associated with higher F1.2 levels among patients not receiving warfarin (R²=.09; P<.0001); the mean F1.2 level for those aged >75 years was 2.5 nmol/L compared with 2.0 nmol/L for those aged 75 years (Table 2). Age was also independently associated with higher F1.2 values in patients receiving warfarin after adjustment for INR intensity and interacted with the inverse of the INR value (R²_change=.03; P<.001). An increase in F1.2 of nearly 0.2 nmol/L (13%) was expected on average for a patient aged 70 years versus a patient aged 60 years for patients with an INR of 1.5. In comparison, with an INR of 3.0 the expected increase for a similar pair of patients was 0.03 nmol/L (5%). In patients with an INR of 2.0, 84% of those aged 75 years had an F1.2 <1.0 nmol/L compared with 61% of those aged >75 years (P=.0003).

In patients not receiving warfarin, F1.2 levels were significantly higher (P=.01) in women than in men (Table 2). This difference remained after adjustment for age (R²_change=.03; P=.01). No difference was seen between men and women in patients receiving warfarin after adjustment for age and INR in the model (R²_change=.003; P=.14).

To further examine the data for the possible effect of venipuncture artifact, we used FPA levels, which were available in a subset of samples (n=478), as a measure of venipuncture quality²⁴ and repeated our analyses in those samples with FPA <22 ng/mL. We chose this cutoff because values up to this level have been described in patients with underlying vascular disease.^{11 25 26} Twenty of 478 samples (4.2%) had FPA 22 ng/mL. In the subset of samples with FPA <22 ng/mL (n=458), the association between F1.2 levels and INR persisted. In patients receiving warfarin (n=360), F1.2 levels were again inversely correlated with INR values, with the relationship F1.2=-0.3+2.5(1/INR) (R²=.45). Higher F1.2 values were again seen in older patients at equivalent INR values. In those patients on aspirin only, the number of patients with F1.2 <1.0 nmol/L was 2 of 98 (2%). In those receiving warfarin, the number of patients with F1.2 values <1.0 nmol/L was 1 of 72 (1%), 12 of 115 (10%), 35 of 71 (49%), 62 of 79 (78%), and 22 of 23 (96%) in those with INR <1.2, 1.2 to 1.4, 1.5 to 1.9, 2.0 to 3.0, and >3.0, respectively (compare with Table 2). Finally, we repeated these analyses with a more conservative FPA cutoff of 6 ng/mL.²⁴ This excluded 73 of 478 samples (15.3%) but did not appreciably change these associations.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Prothrombin fragment 1-2 (F1.2) reflects in vivo thrombin generation.^{7 8 9 10} Our results demonstrate progressive decrease in F1.2 levels as the INR increases, as has been reported by others.^{13 15 16} In accord with other studies of minidose anticoagulation, we found that INR values <2.0 are associated with significant suppression of F1.2.^{16 17} However, patients receiving a dose of warfarin that was not sufficient to increase the INR to >1.2 did not demonstrate measurable suppression of F1.2.

F1.2 levels continued to decrease as the INR increased, and this decline appears to continue as the INR is increased to >3.0. Unfortunately, we did not have a sufficient number of patients with INR >3.0 (n=50) to make definitive conclusions. A recent small series (n=30) did not find any additional suppression of F1.2 in patients with an INR >3.0.¹⁵ The INR range of 2.0 to 3.0 is considered the "therapeutic range" of anticoagulation for most indications¹ and appears to be a good compromise between efficacy and bleeding risk.²⁷ However, a recent subgroup analysis of the European Atrial Fibrillation Trial concluded that an INR >3.0 provides better protection against recurrent vascular events in patients with atrial fibrillation.²⁸ Our results suggest that these higher INR values may be associated with additional suppression of thrombin activity, but the clinical importance of this suppression is uncertain.

These analyses included patients on aspirin, a low fixed dose of warfarin, or standard adjusted-dose warfarin¹⁸ and yielded a wide range of INR values. Because of the design of SPAF III, however, patients on aspirin alone had different clinical characteristics that might affect F1.2 levels. Aspirin patients were younger, more often male, and had less associated cardiovascular disease, characteristics associated with lower F1.2 levels. Thus, the differences in F1.2 between patients on aspirin alone and patients receiving warfarin are likely underestimated. High-risk patients were randomly assigned to combination therapy or adjusted-dose warfarin, and thus the relationship between F1.2 and INR observed in these patients was not biased.

Although there is a strong correlation between F1.2 and INR levels, significant variability remained. Linear regression analysis indicated that approximately 37% of the variability in F1.2 value was related to INR. Even at low INR levels, some patients had low F1.2 values. Among patients with an INR of 1.5 to 1.9, 58 of 137 patients (42%) had an F1.2 <1.0 nmol/L (Table 2). It is possible that these patients might be substantially protected from thromboembolism when maintained in this INR range. At the opposite end of the therapeutic spectrum, even with an INR >3.0 not all patients had F1.2 suppressed to <1.0 nmol/L. This is an important group to examine prospectively, since they hypothetically might be at increased risk of thromboembolism despite "adequate" anticoagulation as defined by INR. Since F1.2 is a more direct measure of thrombin activity, it might be a better index of the effective intensity of anticoagulation. Verification of this hypothesis would require a clinical trial prospectively comparing F1.2 to INR for adjustment of anticoagulation.

Artifact is an important consideration in any study of hemostatic markers. F1.2 levels may be artifactually elevated by traumatic venipuncture through local activation of the coagulation system. In a large study of healthy men aged 50 to 61 years, unsatisfactory venipuncture elevated F1.2 levels by 6% to 13%.²⁴ FPA levels are subject to much greater artifactual elevation and thus have been suggested as a marker for traumatic venipuncture.²⁴ When we excluded samples with elevated FPA levels, the R² for the relationship between F1.2 and INR levels increased somewhat, suggesting that part of the variability we observed when all samples were included was indeed related to venipuncture quality. However, even after those samples with high FPA were excluded, a substantial amount of variability in the relationship remained. Furthermore, the other significant findings of this study, including the relationship between F1.2 and age, persisted in the subgroup of samples with lower FPA levels. The use of an absolute cutoff for excluding samples is somewhat problematic in this population. Excluding samples with FPA >22 ng/mL might eliminate some samples in which the elevation was not artifactual, since atrial fibrillation is a condition predisposing to thrombus formation.

An important finding of this study is that F1.2 levels of older patients remain higher than younger patients at equivalent intensity of anticoagulation as measured by the INR. Several population studies have shown that F1.2 levels increase with age.^{29 30 31} Our results demonstrate that these differences persist among patients receiving warfarin. The clinical significance of this is uncertain, since it is not known whether absolute F1.2 levels are directly related to stroke risk or whether the amount of suppression of F1.2 correlates with stroke risk reduction. Older patients require more intense anticoagulation than younger patients to suppress F1.2 values to the same level. This poses a therapeutic dilemma because older patients are at greater risk for bleeding during anticoagulation,^{20 32 33} and bleeding risk appears to be related to the intensity of anticoagulation as measured by the INR.^{32 33 34} Some have suggested that older people with atrial fibrillation might be maintained at a lower INR,³⁵ and physicians tend to use lower-intensity anticoagulation in these patients.³⁶ In older patients, less intensive anticoagulation (as measured by the INR) would result in even higher F1.2 values.

The reasons for an association between F1.2 and age are not known. Elevated F1.2 levels in older individuals may be related to underlying thrombus formation due to atherosclerosis or other pathophysiological stimuli, or they could indicate that there is an increased need for thrombin generation to maintain vascular integrity and homeostasis in these people. Older patients might also have altered clearance of F1.2. In patients on warfarin, differences in F1.2 levels in older anticoagulated patients may not be solely due to higher baseline F1.2 values but may also reflect differences in warfarin metabolism.

In patients with atrial fibrillation who were not receiving warfarin, we confirmed that women have higher F1.2 levels than men.³⁰ However, among patients receiving warfarin we did not identify a sex-related difference in F1.2 levels. Since women who are not anticoagulated have higher F1.2 values, this suggests that the "relative suppression" of F1.2 is greater in women than in men for an equivalent INR. Interestingly, pooled analysis of clinical trials suggests a slightly greater relative risk reduction in women receiving warfarin, although the difference does not reach conventional statistical significance.³⁷

In summary, we have demonstrated an inverse relationship between F1.2, a marker of thrombin generation, and INR. F1.2 values decrease as the INR increases, but significant variability remains. Older individuals tend to have higher F1.2 levels for equivalent INR levels. The clinical significance of these findings remains uncertain. F1.2 provides additional information regarding the physiological effect of anticoagulation and might be useful for monitoring warfarin therapy. The relationship between F1.2 and stroke is being examined prospectively in the SPAF III study.

	Selected Abbreviations and Acronyms

 

CV = coefficient of variation FPA = fibrinopeptide A INR = international normalized ratio SPAF = Stroke Prevention in Atrial Fibrillation

	Acknowledgments

 
This study was supported by grant R01-NS-24224 from the Division of Stroke and Trauma, National Institute of Neurological Disorders and Stroke, Bethesda, Md. The authors acknowledge the valuable contribution of the SPAF Study Coordinators at the participating institutions who collected the samples for analysis.

	Footnotes

 
Presented in part at the American Heart Association 21st International Joint Conference on Stroke and Cerebral Circulation, San Antonio, Tex, January 25 to 27, 1996.

Received December 4, 1996; revision received March 11, 1997; accepted March 11, 1997.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Hirsh J, Dalen J, Deykin D, Poller L, Bussey H. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 1995;108:231S-246S.[Medline] [Order article via Infotrieve]
2. Bussey H, Force R, Bianco T, Leonard A. Reliance on prothrombin time ratios causes significant errors in anticoagulation therapy. Arch Intern Med. 1993;152:278-282.
3. Hirsh J. Substandard monitoring of warfarin in North America: time for change. Arch Intern Med. 1992;152:257-258.[Medline] [Order article via Infotrieve]
4. Hirsh J, Poller L. The international normalized ratio: a guide to understanding and correcting its problems. Arch Intern Med. 1994;154:282-288.[Abstract]
5. Le D, Weibert R, Sevilla B, Donnelly K, Rapaport S. The international normalized ratio (INR) for monitoring warfarin therapy: reliability and relation to other monitoring methods. Ann Intern Med. 1994;120:552-558.[Abstract/Free Full Text]
6. Lassen J, Kjeldsen J, Antonsen S, Petersen P, Brandslund I. Interpretation of serial measurements of international normalized ratio for prothrombin times in monitoring oral anticoagulant therapy. Clin Chem. 1995;41:1171-1176.[Abstract/Free Full Text]
7. Teitel J, Bauer K, Lau H, Rosenberg R. Studies of the prothrombin activation pathway utilizing radioimmunoassays for the F2/F1+2 fragment and thrombin-antithrombin complex. Blood. 1982;59:1086-1095.[Abstract/Free Full Text]
8. Soria J, Soria C, Mirshahi M, Samama M. Markers of fibrinogen derivatives used in clinical investigation. Semin Thromb Hemost.. 1985;11:129-132.[Medline] [Order article via Infotrieve]
9. Gershlick A. Are there markers of the blood-vessel wall interaction and of thrombus formation that can be used clinically? Circulation. 1990;81(suppl I):I-28-I-34.
10. Pelzer H, Schwarz A, Stuber W. Determination of human prothrombin activation fragment 1+2 in plasma with an antibody against a synthetic peptide. Thromb Haemost.. 1991;65:153-159.[Medline] [Order article via Infotrieve]
11. Merlini P, Bauer K, Oltrona L, Ardissino D, Cattaneo M, Belli C, Mannucci P, Rosenberg R. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation. 1994;90:61-68.[Abstract/Free Full Text]
12. Scharfstein J, Abendschein D, Eisenberg P, George D, Cannon C, Becker R, Sobel B, Cupples L, Braunwald E, Loscalzo J, for the TIMI-5 Investigators. Usefulness of fibrinogenolytic and procoagulant markers during thrombolytic therapy predicting clinical outcomes in acute myocardial infarction. Am J Cardiol. 1996;78:503-510.[Medline] [Order article via Infotrieve]
13. Mannucci P, Bottasso B, Tripodi A, Bonomi A. Prothrombin fragment F1+2 and intensity of treatment with oral anticoagulants. Thromb Haemost.. 1991;66:741. Letter.[Medline] [Order article via Infotrieve]
14. Conway E, Bauer K, Barzegar S, Rosenberg R. Suppression of the hemostatic system activation by oral anticoagulants in the blood of patients with thrombotic diatheses. J Clin Invest. 1987;80:1535-1544.
15. Solymoss S, Bovill E. Markers of in vivo activation of coagulation: interrelationships with change of intensity of oral anticoagulation. Am J Clin Pathol. 1996;105:293-297.[Medline] [Order article via Infotrieve]
16. Kistler J, Singer D, Millenson M, Bauer K, Gress D, Barzegar S, Hughes R, Sheehan M, Maraventano S, Oertle L, Rosner B, Rosenberg R. Effect of low-intensity warfarin anticoagulation on level of activity of the hemostatic system in patients with atrial fibrillation. Stroke. 1993;24:1360-1365.[Abstract/Free Full Text]
17. Millenson M, Bauer K, Kistler J, Barzegar S, Tulin L, Rosenberg R. Monitoring `mini-intensity' anticoagulation with warfarin: comparisons of the prothrombin time using a sensitive thromboplastin with prothrombin fragment F1+2 levels. Blood. 1992;79:2034-2038.[Abstract/Free Full Text]
18. Stroke Prevention in Atrial Fibrillation Investigators. The Stroke Prevention in Atrial Fibrillation III randomized clinical trial: background, design, and clinical characteristics. J Stroke Cerebrovasc Dis. In press.
19. Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet. 1996;348:833-838.
20. Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II study. Lancet. 1994;343:687-691.[Medline] [Order article via Infotrieve]
21. Stroke Prevention in Atrial Fibrillation Investigators. Risk factors for thromboembolism during aspirin therapy in patients with atrial fibrillation: the Stroke Prevention in Atrial Fibrillation study. J Stroke Cerebrovasc Dis. 1995;5:147-157.
22. Tracy R, Bovill E, Stump D, Lin T, Gomol T, Collen D, Mann K. Reduction of in vitro artifact during blood collection in TIMI II. Blood. 1988;78(suppl 1):376. Abstract.
23. Kockum C, Frebelius S. Rapid radioimmunoassay of human fibrinopeptide A: removal of cross-reacting fibrinogen with bentonite. Thromb Res. 1980;19:589-598.[Medline] [Order article via Infotrieve]
24. Miller GJ, Bauer KA, Barzegar S, Foley AJ, Mitchell JP, Cooper JA, Rosenberg RD. The effects of quality and timing of venepuncture on markers of blood coagulation in healthy middle-aged men. Thromb Haemost.. 1995;73:82-86.[Medline] [Order article via Infotrieve]
25. Serneri G, Gensini G, Carnovali M, Prisco D, Rogasi P, Casolo G, Fazi A, Abbate R. Association between time of increased fibrinopeptide A levels in plasma and episodes of spontaneous angina: a controlled prospective study. Am Heart J. 1987;113:672-678.[Medline] [Order article via Infotrieve]
26. Ardissino D, Merlini P, Gamba G, Barberis P, Demicheli G, Testa S, Colombi E, Poli A, Fetiveau R, Montemartini C. Thrombin activity and early outcome in unstable angina pectoris. Circulation. 1996;93:1634-1639.[Abstract/Free Full Text]
27. Hylek E, Skates S, Sheehan M, Singer D. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med. 1996;335:540-546.[Abstract/Free Full Text]
28. European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med. 1995;333:5-10.[Abstract/Free Full Text]
29. Bauer KA, Weiss LM, Sparrow D, Vokonas PS, Rosenberg RD. Aging-associated changes in indices of thrombin generation and protein C activation in humans. J Clin Invest. 1987;80:1527-1534.
30. Cushman M, Psaty B, Macy E, Bovill E, Cornell E, Kuller L, Tracy R. Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease. Arterioscler Thromb Vasc Biol. 1996;16:1163-1169.[Abstract/Free Full Text]
31. Hursting MJ, Stead AG, Crout FV, Horvath BZ, Moore BM. Effects of age, race, sex, and smoking on prothrombin fragment 1.2 in a healthy population. Clin Chem. 1993;39:683-686.[Abstract/Free Full Text]
32. Stroke Prevention in Atrial Fibrillation Investigators. Bleeding during antithrombotic therapy in patients with atrial fibrillation: the Stroke Prevention in Atrial Fibrillation study. Arch Intern Med. 1996;156:409-416.[Abstract]
33. Fihn S, Callahan C, Martin D, McDonell M, Henikoff J, White R, for the National Consortium of Anticoagulation Clinics. The risk for and severity of bleeding complications in elderly patients treated with warfarin. Ann Intern Med. 1996;124:970-979.[Abstract/Free Full Text]
34. Levine M, Raskob G, Landefeld S, Hirsh J. Hemorrhagic complications of anticoagulant treatment. Chest. 1995;108:276S-290S.[Medline] [Order article via Infotrieve]
35. Blackshear J, Kopecky S, Litin S, Safford R, Hammill S. Management of atrial fibrillation in adults: prevention of thromboembolism and symptomatic treatment. Mayo Clin Proc. 1996;71:150-160.[Medline] [Order article via Infotrieve]
36. McCrory D, Matchar D, Samsa G, Sanders L, Pritchett E. Physician attitudes about anticoagulation for nonvalvular atrial fibrillation in the elderly. Arch Intern Med. 1995;155:277-281.[Abstract]
37. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154:1449-1457.[Abstract]

This article has been cited by other articles:

				Writing Committee Members, V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 651 - 745. [Full Text] [PDF]

				V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society J. Am. Coll. Cardiol., August 15, 2006; 48(4): e149 - e246. [Full Text] [PDF]

				V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society Circulation, August 15, 2006; 114(7): e257 - e354. [Full Text] [PDF]

				K. L. Furie, R. Rosenberg, J. L. Thompson, K. Bauer, J. P. Mohr, B. Rosner, R. Sciacca, S. Barzegar, B. Thornell, T. Costigan, et al. Thrombin generation in non-cardioembolic stroke subtypes: The Hemostatic System Activation Study Neurology, September 14, 2004; 63(5): 777 - 784. [Abstract] [Full Text] [PDF]

				A. Abidov, R. Hachamovitch, A. Rozanski, S. W. Hayes, M. M. Santos, M. G. Sciammarella, I. Cohen, J. Gerlach, J. D. Friedman, G. Germano, et al. Prognostic implications of atrial fibrillation in patients undergoing myocardial perfusion single-photon emission computed tomography J. Am. Coll. Cardiol., September 1, 2004; 44(5): 1062 - 1070. [Abstract] [Full Text] [PDF]

				R. Kanagala, N. S. Murali, P. A. Friedman, N. M. Ammash, B. J. Gersh, K. V. Ballman, A. S. M. Shamsuzzaman, and V. K. Somers Obstructive Sleep Apnea and the Recurrence of Atrial Fibrillation Circulation, May 27, 2003; 107(20): 2589 - 2594. [Abstract] [Full Text] [PDF]

				V. Fuster, L. E. Ryden, R. W. Asinger, D. S. Cannom, H. J. Crijns, R. L. Frye, J. L. Halperin, G. N. Kay, W. W. Klein, S. Levy, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology Circulation, October 23, 2001; 104(17): 2118 - 2150. [Full Text] [PDF]

				Guidelines for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to develop guidelines for the management of patients with atrial fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology Eur. Heart J., October 2, 2001; 22(20): 1852 - 1923. [PDF]

				V. Fuster, L. E. Ryden, R. W. Asinger, D. S. Cannom, H. J. Crijns, R. L. Frye, J. L. Halperin, G. N. Kay, W. W. Klein, S. Levy, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary: A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1231 - 1265. [Full Text] [PDF]

				V. Fuster, L. E. Ryden, R. W. Asinger, D. S. Cannom, H. J. Crijns, R. L. Frye, J. L. Halperin, G. N. Kay, W. W. Klein, S. Levy, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1266 - 1266. [Full Text] [PDF]

				R. Cote, C. Wolfson, S. Solymoss, A. Mackey, J. R Leclerc, D. Simard, F. Rouah, F. Bourque, and B. Leger Hemostatic Markers in Patients at Risk of Cerebral Ischemia Stroke, August 1, 2000; 31(8): 1856 - 1862. [Abstract] [Full Text] [PDF]

				W. M. Feinberg, L. A. Pearce, R. G. Hart, M. Cushman, E. S. Cornell, G. Y.H. Lip, and E. G. Bovill Markers of Thrombin and Platelet Activity in Patients With Atrial Fibrillation : Correlation With Stroke Among 1531 Participants in the Stroke Prevention in Atrial Fibrillation III Study Stroke, December 1, 1999; 30(12): 2547 - 2553. [Abstract] [Full Text] [PDF]

				R. G. Hart and J. L. Halperin Atrial Fibrillation and Thromboembolism: A Decade of Progress in Stroke Prevention Ann Intern Med, November 2, 1999; 131(9): 688 - 695. [Abstract] [Full Text] [PDF]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Feinberg, W. M. Articles by Bovill, E. G. Search for Related Content PubMed PubMed Citation Articles by Feinberg, W. M. Articles by Bovill, E. G.