Use Of Fibrinogen and Fibrin D-Dimer in Prediction of Arterial Thrombotic Events

Introduction

There is increasing clinical and laboratory interest in the measurement of both plasma fibrinogen and fibrin D-dimer to predict arterial thrombotic events, such as cardiovascular death, myocardial infarction (MI), stroke, leg ischemia, arterial surgery (e.g., angioplasty, bypass grafting), and postsurgical arterial occlusion. There are several possible reasons for such interest.

First, there is substantial evidence from prospective studies that the plasma fibrinogen level is a strong, consistent predictor of such cardiovascular events in people with or without clinically detectable arterial disease. Furthermore, fibrinogen adds to the predictive valve of major conventional risk predictors (e.g., smoking, blood pressure, serum cholesterol) in healthy people (Fig.1).^1-7

Second, we and others have shown, in several prospective studies, that plasma fibrin D-dimer (measured quantitatively by enzyme-linked immunosorbent assays [ELISAs]) is also a strong, consistent predictor of such cardiovascular events in people with or without clinically detectable arterial disease.^8-14 Again, fibrin D-dimer may add to the predictive value of major conventional risk predictors (e.g., smoking, blood pressure, serum cholesterol, plasma fibrinogen) in healthy people (Fig. 2).

Third, there are several interactive, plausible, potential biological mechanisms through which increasing plasma fibrinogen levels, which are due to multiple gene-environment interactions, may promote ischemic events. These include increased blood viscosity, atherogenesis, and platelet-fibrin thrombogenesis (Fig. 3). Increased plasma D-dimer levels are a marker of turnover of cross-linked fibrin, whether vascular or extravascular (Fig. 3).

Fourth, not only is there more evidence for fibrinogen and D-dimer as predictors of arterial thrombotic events than for other hemostatic or thrombotic variables, but these two assays are more stable and more practical to measure in clinical and epidemiological studies. These tests are also already available in many district hospitals for the diagnosis of disseminated intravascular coagulation (DIC) and, in the case of D-dimer, venous thromboembolism.^15,16 As with other major cardiovascular risk factors (e.g., smoking, blood pressure, serum cholesterol), there is a need for standardization of both fibrinogen assays^17-23 and D-dimer assays.²⁴

Finally, clinical interest in plasma assays of fibrinogen also may increase in the event that ongoing clinical trials of plasma fibrinogen reduction (e.g., with certain fibrates or ancrod) show that such treatments are beneficial.²⁵ Likewise, clinical interest in plasma assays of D-dimer may also increase if future studies show that oral anticoagulant prophylaxis is the most costeffective and risk-effective in people with elevated plasma D-dimer levels, who are normalized by full-dose warfarin.^15,19,26-28 This review discusses each of these aspects of fibrinogen and fibrin D-dimer.

• References

• 1 Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993; 118: 956-963.
• 2 Heinrich H, Balleisen L, Schulte H, Assmann G, van de Loo J.. Fibrinogen and factor VII in the prediction of coronary risk. Results from the PROCAM Study in healthy men. Arterioscler Thromb Vasc Biol 1994; 14: 54-59.
• 3 Lowe GDO. Fibrinogen. A cardiovascular risk factor. 2d ed.. Mannheim: Boehringer Mannheim; 1997
• 4 Kannel EB, D’Agostino RB, Belanger AJ. Update of fibrinogen as a cardiovascular risk factor. Ann Epidemiol 1992; 2: 457-466.
• 5 Kannel WB. Influence of fibrinogen on cardiovascular disease. Drugs 1997; 54 (Suppl. 03) 32-40.
• 6 Danesh J, Collins R, Appleby P, Peto R. Fibrinogen, C-reactive protein, albumin or white cell count: meta-analyses of prospective studies of coronary heart disease. JAMA 1998; 279: 1477-1482.
• 7 Woodward M, Lowe GDO, Rumley A, Tunstall-Pedoe H. Fibrinogen as a risk factor for coronary heart disease and mortality in middle aged men and women: The Scottish Heart Health Study. Eur Heart J 1998; 19: 55-62.
• 8 Cortellaro M, Confrancesco E, Boschetti C, Mussoni L, Donati MB, Cardillo M, Catalano M, Gabrielli L, Lombardi B, Specchia G, et al. Increased fibrin turnover and high PAI-1 activity as predictors of ischaemic events in atherosclerotic patients: a case-control study. Arterioscler Thromb Vasc Biol 1993; 13: 1412-1417.
• 9 Fowkes FGR, Lowe GDO, Housely E, Rattray A, Elton RA, MacGregor IR, Dawes J. Cross-linked fibrin degradation products, risk of coronary heart disease, and progression of peripheral arterial disease. Lancet 1993; 342: 84-86.
• 10 Ridker PM, Hennekens CH, Cerskus A, Stampfer MH. Plasma concentration of cross-linked fibrin degradation products (D-dimer) and the risk of future myocardial infarction among apparently health men. Circulation 1984; 90: 2236-2240.
• 11 Woodburn KR, Rumley A, Lowe GDO, Love JG, Murray GD, Pollock JG. Clinical, biochemical and rheologic factors affecting the outcome of infrainguinal bypass grafting. J Vasc Surg 1996; 24: 639-646.
• 12 Smith FB, Lee AJ, Fowkes FGR, Rumley A, Lowe GDO. Hemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study. Arterioscler Thromb Vasc Biol 1997; 17: 3321-3325.
• 13 Lowe GDO, Yarnell JWG, Sweetnam PM, Rumley A, Thomas HF, Elwood PC. Fibrin D-dimer, tissue plasminogen activator, plasminogen activator inhibitor, and the risk of major ischaemic heart disease in the Caerphilly Study. Thromb Haemost 1998; 79: 129-133.
• 14 Smith FB, Rumley A, Lee AJ, Leng GL, Fowkes FGR, Lowe GDO. Haemostatic factors and prediction of ischaemic heart disease and stroke in claudicants. Br J Haematol 1998; 100: 758-763.
• 15 Lip GYH, Lowe GDO. Fibrin D-dimer: a useful clinical marker of thrombogenesis?. Clin Sci (Colch) 1995; 89: 205-214.
• 16 Bounameaux H, de Moerloose P, Perrier A, Miron M-J. D-dimer testing in suspected venous thromboembolism: an update. QJM 1997; 90: 422-437.
• 17 Furlan M, Felix R, Escher N, Lämmle B. How high is the true fibrinogen content of fibrinogen standards?. Thromb Res 1989; 56: 583-592.
• 18 Gaffney PJ, Wong MY. Collaborative study of proposed international standard for plasma fibrinogen measurement. Thromb Haemost 1992; 68: 428-432.
• 19 Lowe GDO. Haemostatic risk factors for arterial and venous thrombosis. In: Recent Advances in Blood Coagulation, 7. Poller L, Ludlam CA. eds. Edinburgh: Churchill Livingstone; 1997: 69-96.
• 20 Sweetnam PM, Yarnell JWG, Lowe GDO, Baker IA, O’Brien JR, Rumley A, Etherington MD, Whitehead PJ, Elwood PC. The relative power of heat-precipitation nephelometric and clottable (Clauss) fibrinogen in the prediction of ischaemic heart disease: the Caerphilly and Speedwell studies. Br J Haematol 1998; 100: 582-588.
• 21 Lawrie AS, Mackie IJ, Kitchen S, Howarth D, Martin J, Gaffney P, Rigsby P, Rumley A, Lowe G. An evaluation of popular Clauss and prothrombin time derived fibrinogen assay reagents. Blood Coag Fibrinolysis 1999; 10 (Suppl. 01) s101-102.
• 22 Mackie IJ, Lawrie AS, Howarth D, Martin J, Rumley A, Lowe G, Gaffney P, Rigsby P, Kitchen S. The impact of commercial reference preparations on fibrinogen assays. Blood Coagul Fibrinolysis 1999; 10 (Suppl. 01) s102.
• 23 Rumley A, Woodward M, Hoffmeister A, Koenig W, Lowe GDO. Comparison of three plasma fibrinogen assays in a random population sample. Blood Coagul Fibrinolysis 1999; 10 (Suppl. 01) s102.
• 24 Gaffney PJ, Edgell T, Creighton-Kempsford LJ, Wheeler S, Tarelli E. Fibrin degradation product (FnDP) assays: analysis of standardisation issues and target antigens in plasma. Br J Haematol 1995; 90: 187-194.
• 25 Lowe GDO. Agents lowering blood viscosity, including defibrinogenating agents. In: Cardiovascular Thrombosis. 2d ed.. Verstralte M, Fuster V, Topol EJ. eds. Philadelphia: Lippincott-Raven; 1998: 321-333.
• 26 Lip GYH, Lowe GDO, Rumley A, Dunn FG. Increased markers of thrombogenesis in chronic atrial fibrillation: effects of warfarin treatment. Br Heart J 1995; 73: 527-533.
• 27 Lip GYH, Lowe GDO, Metcalfe MJ, Rumley A, Dunn FG. Effects of warfarin therapy on plasma fibrinogen, von Willebrand factor, and fibrin D-dimer in left ventricular dysfunction secondary to coronary artery disease with and without aneurysms. Am J Cardiol 1995; 76: 453-458.
• 28 Lip GYH, Zafiris J, Watson RDS, Bareford D, Lowe GDO, Beevers DG. Fibrin D-dimer and β-thromboglobulin as markers of thrombogenesis and platelet activation in atrial fibrillation. Effects of introducing ultra-low-dose warfarin and aspirin. Circulation 1996; 94: 425-431.
• 29 Meade TW, North WRS, Chakrabarti R, Stirling Y, Haines AP, Thompson SG, Brozovie M. Haemostatic function and cardiovascular death: early results of a prospective study. Lancet 1980; i: 1050-1054.
• 30 Resch KL, Ernst E. The complex impact of fibrinogen on atherosclerosis-related diseases. In: Koenig W, Hombäck V, Bond MG, Dramsch DM. eds. Progression and Regression of Atherosclerosis. Vienna: Blackwell MZV; 1995: 36-40.
• 31 Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984; 311: 501-505.
• 32 Lowe GDO, Lee AJ, Rumley A, Price JF, Fowkes FG. Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study. Br J Haematol 1997; 96: 168-173.
• 33 Tanne D, Benderly M, Boyko V, et al. Fibrinogen is an independent predictor of stroke-TIA in patients with coronary heart disease. Blood Coagul Fibrinolysis 1994; 5 (Suppl. 02) Abstract 0-52.
• 34 Banton D, Sweetnam P, Baker I, Elwood P. Peripheral vascular disease. Consequence for survival and association with risk factors in the Speedwell Prospective Heart Disease Study. Br Heart J 1994; 72: 128-132.
• 35 Montalescot G, Ankri A, Vicant E, Drobinski G, Grosgogeat Y, Thomas D. Fibrinogen after coronary angioplasty as a risk factor for restenosis. Circulation 1995; 92: 31-38.
• 36 Stein D, Schoebel FC, Heins M, et al. Lipoprotein(a) and fibrinogen in restenosis after percutaneous transluminal coronary angioplasty. Clin Hemorheol 1995; 15: 737-747.
• 37 Wiseman S, Kenchington G, Dain R, Marshall CE, McCollum CN, Greenhalgh RM, Powell JT. Influence of smoking and plasma factors on patency of femoropopliteal vein grafts. Br Med J 1989; 299: 643-646.
• 38 Grotta JC, Yatsu TM, Pettigrew LC, Rhoades H, Bratina P, Vital D, Alam R, Earls R, Picone C. Prediction of carotid stenosis progression by lipid and hematologic measurements. Neurology 1989; 39: 1325-1331.
• 39 Lee AJ, Mowbray PI, Lowe GDO, Rumley A, Fowkes FGR, Allan PL. Blood viscosity and elevated carotid intima-media thickness in men and women: the Edinburgh Artery Study. Circulation 1998; 97: 1467-1473.
• 40 Lee AJ, Smith WCS, Lowe GDO, Tunstall-Pedoe H. Plasma fibrinogen and coronary risk factors: the Scottish Heart Health Study. J Clin Epidemiol 1990; 43: 913-919.
• 41 Lee AJ, Lowe GDO, Smith WCS, Tunstall-Pedoe H. Plasma fibrinogen in women; relationships with oral contraception, the menopause and hormone replacement therapy. Br J Haematol 1993; 83: 616-621.
• 42 Lee AJ, Lowe GDO, Woodward M, Tunstall-Pedoe H. Fibrinogen in relation to personal history of prevalent hypertension, diabetes, stroke, intermittent claudication, coronary heart disease and family history: the Scottish Heart Health Study. Br Heart J 1993; 69: 338-342.
• 43 Tunstall-Pedoe H, Woodward M, Tavendale R, D’A Brook R, McCluskey MK. Comparison of the prediction by 27 different risk factors of coronary heart disease and death in men and women of the Scottish Heart Health Study. BMJ 1997; 315: 722-729.
• 44 International Task Force. Prevention of coronary heart disease: scientific background and new clinical guidelines. Recommendations of the European Atherosclerosis Society. Nutr Metabol Cardiovasc Dis 1992; 2: 113-565.
• 45 Rumley A, Lowe GDO, Norrie J, Ford I, Shepherd J, Cobbe SM. Blood rheology and outcome in the west of Scotland coronary prevention study. Br J Haematol 1997; 97 (Suppl. 01) 78.
• 46 Califf RM, Armstrong PW, Carver IR, D’Agostino RB, Strauss WE. 27^th Bethesda Conference: matching the intensity of risk factor management with the hazard for coronary disease events. Task force 5. Stratification of patients into high, medium and low risk sub-groups for purposes of risk factor management. J Am Coll Cardiol 1996; 27 (05) 1007-1019.
• 47 Lowe G.D.O.. Prediction of postoperative deep vein thrombosis. Thromb Haemost 1997; 78: 47-52.
• 48 Reid D. 1991. The clinical role of fibrinogen and fibrin in peripheral arterial disease. MD Thesis University of Glasgow.;
• 49 Al-Zahrani H, Lowe GDO, Douglas JT. et al Increased fibrin turnover in peripheral arterial disease: comparison with a population study. Clin Hemorheol 1992; 12: 867-872.
• 50 Smith FB, Lowe GDO, Fowkes FGR, Rumley A, Rumley AG, Donnan PT, Housley E. Smoking, haemostatic factors and lipid peroxides in a population case-control study of peripheral arterial disease. Atherosclerosis 1993; 102: 155-162.
• 51 Rumley A, Woodburn KR, Lowe GDO. et al Correlation between plasma fibrinogen, fibrin degradation products, and the angiographic extent of peripheral arterial occlusive disease. Blood Coag Fibrinolysis 1994; 5 (Suppl. 02) 38.
• 52 Lee AJ, Fowkes FGR, Lowe GDO, Rumley A. Fibrin D-dimer, haemostatic factors and peripheral arterial disease. Thromb Haemost 1995; 74: 828-832.
• 53 Lee AJ, Fowkes FGR, Lowe GDO, Rumley A. Determinants of fibrin D-dimer in the Edinburgh Artery Study. Arterioscler Thromb Vasc Biol 1995; 15: 1094-1097.
• 54 Sweetnam PM, Thomas HF, Yarnell JWG, Beswick AD, Baker IA. Elwood PC. Fibrinogen, viscosity and the 10-year incidence of ischaemic heart disease. The Caerphilly and Speedwell studies. Eur Heart J 1996; 17: 1814-1820.
• 55 Lee AJ, Fowkes FGR, Lowe GDO, Rumley A. Haemostatic factors, atherosclerosis and risk of abdominal aortic aneurysm. Blood Coagul Fibrinolysis 1996; 7: 695-701.
• 56 Lip GYH, Rumley A, Dunn FG, Lowe GDO. Plasma fibrinogen and fibrin D-dimer in patients with atrial fibrillation: effects of cardioversion to sinus rhythm. Int J Cardiol 1995; 51: 245-251.
• 57 Nieuwenhuizen W. Biochemistry and measurement of fibrinogen. Eur Heart J 1995; 16 suppl. A 6-10.
• 58 de Maat MPM, Lowe GDO, Haverkate F. Fibrinogen. In: Laboratory Techniques in Thrombosis, A Manual. 2d rev ed. of ECAT Assay Procedures Jespersen J, Bertina RM, Haverkate F. eds. Dordrecht: Kluwer; 1999: 79-88.
• 59 Lowe GDO, Rumley A, Woodward M, Morrison CE, Philippou H, Lane DA, Tunstall-Pedoe H. Epidemiology of coagulation factors, inhibitors and activation markers: The Third Glasgow MONICA Survey. I. Illustrative reference ranges by age, sex and hormone use. Br J Haematol 1997; 97: 775-784.
• 60 Woodward M, Lowe GDO, Rumley A, Tunstall-Pedoe H, Philippou H, Lane A, Morrison CE. Epidemiology of coagulation factors, inhibitors and activation markers: The Third Glasgow MONICA Survey. II. Relationships to cardiovascular risk factors and prevalent cardiovascular disease. Br J Haematol 1997; 97: 785-797.
• 61 Rosenson RS, Tangrey CC, Hafner JM. Intra-individual variability of fibrinogen levels and cardiovascular risk profile. Arterioscler Thromb Vasc Biol 1994; 14: 1928-1932.
• 62 Niewenhuizen W, Bos R. Soluble fibrin and degradation products of fibrinogen (Fg DP), fibrin (FbDP; D-dimer) and total of FgDP and FbDP (TDP). In: Laboratory Techniques in Thrombosis, A Manual. 2d rev ed. of ECAT Assay Procedures Jespersen J, Bertina RM, Haverkate F. eds. Dordrecht: Kluwer; 1999: 275-284.