Download PDF
Thromb Haemost 2001; 86(01): 366-373
DOI: 10.1055/s-0037-1616234
Research Article
Schattauer GmbH

Hemostatic Risk Factors for Atherothrombotic Disease: An Epidemiologic View

Aaron R. Folsom
1   Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, MN, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
12 December 2017 (online)

    Permissions and Reprints

Summary

A number of prospective epidemiologic studies have now tested the hypothesis that plasma measures of hemostatic factors measured in initially healthy subjects may predict the future onset of atherothrombotic events. Epidemiologic evidence is very strong that plasma fibrinogen is a risk marker, if not a causal factor, for atherothrombotic events. Evidence is mixed on whether factor VII, factor VIII, von Willebrand factor, or other coagulation markers predict incident atherothrombosis. D-dimer is emerging as a strong risk marker, as are several fibrinolytic markers such as tPA antigen – but not PAI-1. Despite suggestive studies, no genetic polymorphism influencing hemostatic factor levels has emerged as a consistent and strong risk factor for atherothrombosis. Thus, prospective epidemiologic studies have identified several potential hemostatic markers of atherothrombosis risk, but their causal role and clinical utility in risk prediction remain incompletely established.

Key words

Atherosclerosis - coronary disease - fibrinogen - fibrinolysis - coagulation factors
 

  • References

  • 1 Folsom AR, Rosamond WD, Shahar E, Cooper LS, Aleksic N, Nieto FJ, Rasmussen ML, Wu KK. Prospective study of markers of hemostatic function with risk of ischemic stroke. Circulation 1999; 100: 736-42.
    CrossrefPubMedGoogle Scholar
  • 2 Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless LE. Prospective study of hemostatic factors and incidence of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 1997; 96: 1102-8.
    CrossrefPubMedGoogle Scholar
  • 3 Cambien F. Genetic prediction of myocardial infarction. Blood Coagul Fibrinolysis 1999; 10 (Suppl. 01) S23-4.
    CrossrefPubMedGoogle Scholar
  • 4 Grant PJ, Humphries SE. Genetic determinants of arterial thrombosis. Baillieres Best Pract Res Clin Haematol 1999; 12: 505-32.
    CrossrefPubMedGoogle Scholar
  • 5 Manzoli A, Andreotti F, Leone AM, Sperti G, Zecchi P, Di Sciascio G. Vascular and haemostatic gene polymorphisms associated with non-fatal myocardial infarction: a critical review. Ital Heart J 2000; 1: 184-93.
    PubMedGoogle Scholar
  • 6 Salomaa V, Stinson V, Kark JD, Folsom AR, Davis CE, Wu KK. Association of fibrinolytic parameters with early atherosclerosis. The ARIC Study. Circulation 1995; 91: 284-90.
    CrossrefPubMedGoogle Scholar
  • 7 Antiplatelet Trialists’ Collaboration.. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81-106.
    CrossrefPubMedGoogle Scholar
  • 8 Thaulow E, Erikssen J, Sandvik L, Stormorken H, Cohn PF. Blood platelet count and function are related to total and cardiovascular death in apparently healthy men. Circulation 1991; 84: 613-7.
    CrossrefPubMedGoogle Scholar
  • 9 Meade TW, Cooper JA, Miller GJ. Platelet counts and aggregation measures in the incidence of ischaemic heart disease (IHD). Thromb Haemost 1997; 78: 926-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Zhu MM, Weedon J, Clark LT. Meta-analysis of the association of platelet glycoprotein IIIa PlA1/A2 polymorphism with myocardial infarction. Am J Cardiol 2000; 86: 1000-5.
    CrossrefPubMedGoogle Scholar
  • 11 Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: Meta-analyses of prospective studies. JAMA 1998; 279: 1477-82.
    CrossrefPubMedGoogle Scholar
  • 12 Folsom AR, Wu KK, Davis CE, Conlan MG, Sorlie PD, Szklo M. for the Atherosclerosis Risk in Communities (ARIC) Study Investigators.. Population correlates of plasma fibrinogen and factor VII, putative cardiovascular risk factors. Atherosclerosis 1991; 91: 191-205.
    CrossrefPubMedGoogle Scholar
  • 13 Tracy RP, Arnold AM, Ettinger W, Fried L, Meilahn E, Savage P. The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study. Arterioscler Thromb Vasc Biol 1999; 19: 1776-83.
    CrossrefPubMedGoogle Scholar
  • 14 Ma J, Hennekens CH, Ridker PM, Stampfer MJ. A prospective study of fibrinogen and risk of myocardial infarction in the Physicians’ Health Study. J Am Coll Cardiol 1999; 33: 1347-52.
    CrossrefPubMedGoogle Scholar
  • 15 Sato S, Nakamura M, Iida M, Naito Y, Kitamura A, Okamura T, Nakagawa Y, Imano H, Kiyama M, Iso H, Shimamoto T, Komachi Y. Plasma fibrinogen and coronary heart disease in urban Japanese. Am J Epidemiol 2000; 152: 420-3.
    CrossrefPubMedGoogle Scholar
  • 16 Cooper JA, Miller GJ, Bauer KA, Morrissey JH, Meade TW, Howarth DJ, Barzegar S, Mitchell JP, Rosenberg RD. Comparison of novel hemostatic factors and conventional risk factors for prediction of coronary heart disease. Circulation 2000; 102: 2816-22.
    CrossrefPubMedGoogle Scholar
  • 17 Smith FB, Lee AJ, Hau CM, Rumley A, Lowe GD, Fowkes FG. Plasma fibrinogen, haemostatic factors and prediction of peripheral arterial disease in the Edinburgh Artery Study. Blood Coagul Fibrinolysis 2000; 11: 43-50.
    CrossrefPubMedGoogle Scholar
  • 18 Maresca G, Di Blasio A, Marchioli R, Di Minno G. Measuring plasma fibrinogen to predict stroke and myocardial infarction: an update. Arterioscler Thromb Vasc Biol 1999; 19: 1368-77.
    CrossrefPubMedGoogle Scholar
  • 19 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: 501-5.
    CrossrefPubMedGoogle Scholar
  • 20 Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease: the Framingham Study. JAMA 1987; 258: 1183-6.
    CrossrefPubMedGoogle Scholar
  • 21 Smith FB, Lee AJ, Fowkes FG, Price JF, Rumley A, Lowe GD. Hemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study. Arterioscler Thromb Vasc Biol 1997; 17: 3321-5.
    CrossrefPubMedGoogle Scholar
  • 22 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WR, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 2: 533-7.
    PubMedGoogle Scholar
  • 23 Danesh J, Collins R, Peto R, Lowe GDO. Haematocrit, viscosity, erythrocyte sedimentation rate: meta-analyses of prospective studies of coronary heart disease. Eur Heart J 2000; 21: 515-20.
    CrossrefPubMedGoogle Scholar
  • 24 Morrow DA, Ridker PM. C-reactive protein, inflammation, and coronary risk. Med Clin North Am 2000; 84: 149-61.
    CrossrefPubMedGoogle Scholar
  • 25 Packard CJ, O’Reilly DS, Caslake MJ, McMahon AD, Ford I, Cooney J, Macphee CH, Suckling KE, Krishna M, Wilkinson FE, Rumley A, Lowe GD. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. N Engl J Med 2000; 343: 1148-55.
    CrossrefPubMedGoogle Scholar
  • 26 Heinrich J, Balleisen L, Schulte H, Assmann G, van de Loo J. Fibrinogen and factor VII in the prediction of coronary risk: results form the PROCAM Study in Healthy Men. Arterioscler Thromb 1994; 14: 54-9.
    CrossrefPubMedGoogle Scholar
  • 27 Junker R, Heinrich J, Schulte H, van de Loo J, Assmann G. Coagulation factor VII and the risk of coronary heart disease in healthy men. Arterioscler Thromb Vasc Biol 1997; 17: 1539-44.
    CrossrefPubMedGoogle Scholar
  • 28 Miller GJ, Stirling Y, Esnouf MP, Heinrich J, van de Loo J, Kienast J, Wu KK, Morrissey JH, Meade TW, Martin JC. Factor VII-deficient substrate plasmas depleted of protein C raise the sensitivity of the factor VII bioassay to activated factor VII: an international study. Thromb Haemost 1994; 71: 38-48.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Ruggeri ZM, Ware J. The structure and function of von Willebrand factor. Thromb Haemost 1992; 67: 594-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Blann A. von Willebrand factor and the endothelium in vascular disease. Br J Biomed Sci 1993; 50: 125-34.
    PubMedGoogle Scholar
  • 31 Meade TW, Cooper JA, Stirling Y, Howarth DJ, Ruddock V, Miller GJ. Factor VIII ABO blood group and the incidence of ischaemic heart disease. Br J Haematol 1994; 88: 601-7.
    CrossrefPubMedGoogle Scholar
  • 32 Rumley A, Lowe GD, Sweetnam PM, Yarnell JW, Ford RP. Factor VIII von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Heart Study. Br J Haematol 1999; 105: 110-6.
    CrossrefPubMedGoogle Scholar
  • 33 Thogersen AM, Jansson JH, Boman K, Nilsson TK, Weinehall L, Huhtasaari F, Hallmans G. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: Evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98: 2241-7.
    CrossrefPubMedGoogle Scholar
  • 34 Meade TW, Cooper JA, Chakrabarti R, Miller GJ, Stirling Y, Howarth DJ. Fibrinolytic activity and clotting factors in ischaemic heart disease in women. BMJ 1996; 312: 1581.
    CrossrefPubMedGoogle Scholar
  • 35 Folsom AR, Aleksic N, Park E, Salomaa V, Juneja H, Wu KK. A prospective study of fibrinolytic factors and incidence of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) Study. In Press
    PubMedGoogle Scholar
  • 36 Salomaa V, Matei C, Aleksic N, Sansores-Carcia L, Folsom AR, Juneja H, Chambless LE, Wu KK. Soluble thrombomodulin as a predictor of incident coronary heart disease: The ARIC Study. Lancet 1999; 353: 1729-34.
    CrossrefPubMedGoogle Scholar
  • 37 Iacoviello L, Di Castelnuovo A, De Knijff P, D’Orazio A, Amore C, Arboretti R, Kluft C, Donati M. Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction. N Engl J Med 1998; 338: 79-85.
    CrossrefPubMedGoogle Scholar
  • 38 Girelli D, Russo C, Ferraresi P, Olivieri O, Pinotti M, Friso S, Manzato F, Mazzucco A, Bernardi F, Corrocher R. Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease. N Engl J Med 2000; 343: 774-80.
    CrossrefPubMedGoogle Scholar
  • 39 Wang W, Boffa MB, Bajzar L, Walker JB, Nesheim ME. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor. J Biol Chem 1998; 273: 27176-81.
    CrossrefPubMedGoogle Scholar
  • 40 Collen D. The plasminogen (fibrinolytic) system. Thromb Haemost 1999; 82: 259-70.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076-9.
    CrossrefPubMedGoogle Scholar
  • 42 Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-8.
    CrossrefPubMedGoogle Scholar
  • 43 Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994; 343: 940-3.
    CrossrefPubMedGoogle Scholar
  • 44 Lowe GD, Yarnell JW, 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. Thromb Haemost 1998; 79: 129-33.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Gram J, Bladbjerg EM, Moller L, Sjol A, Jespersen J. Tissue-type plasminogen activator and C-reactive protein in acute coronary heart disease. A nested case-control study. J Intern Med 2000; 247: 205-12.
    CrossrefPubMedGoogle Scholar
  • 46 Johansson L, Jansson JH, Boman K, Nilsson TK, Stegmayr B, Hallmans G. Tissue plasminogen activator, plasminogen activator inhibitor-1, and tissue plasminogen activator/plasminogen activator inhibitor-1 complex as risk factors for the development of a first stroke. Stroke 2000; 31: 26-32.
    CrossrefPubMedGoogle Scholar
  • 47 Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. A prospective study of plasminogen activator inhibitor and the risk of future myocardial infarction. Circulation 1992; 85 (Suppl. 01) I-325 (abstr).
    PubMedGoogle Scholar
  • 48 Cushman M, Lemaitre RN, Kuller LH, Psaty BM, Macy EM, Sharrett AR, Tracy RP. Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1999; 19: 493-8.
    CrossrefPubMedGoogle Scholar
  • 49 Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332: 635-41.
    CrossrefPubMedGoogle Scholar
  • 50 Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9.
    PubMedGoogle Scholar
  • 51 Juhan-Vague I, Pyke SD, Alessi MC, Jespersen J, Haverkate F, Thompson SG. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation 1996; 94: 2057-63.
    CrossrefPubMedGoogle Scholar
  • 52 Gram J, Jespersen J. A selective depression of tissue plasminogen activator (t-PA) activity in euglobulins characterises a risk group among survivors of acute myocardial infarction. Thromb Haemost 1987; 57: 137-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Munkvad S, Gram J, Jespersen J. A depression of active tissue plasminogen activator in plasma characterizes patients with unstable angina pectoris who develop myocardial infarction. Eur Heart J 1990; 11: 525-8.
    CrossrefPubMedGoogle Scholar
  • 54 Jansson JH, Nilsson TK, Olofsson BO. Tissue plasminogen activator and other risk factors as predictors of cardiovascular events in patients with severe angina pectoris. Eur Heart J 1991; 12: 157-61.
    CrossrefPubMedGoogle Scholar
  • 55 Jansson JH, Olofsson BO, Nilsson TK. Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary artery disease. A 7-year follow-up. Circulation 1993; 88: 2030-4.
    CrossrefPubMedGoogle Scholar
  • 56 Cortellaro M, Cofrancesco 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 ischemic events in atherosclerotic patients. A case-control study. Arterioscler Thromb 1993; 13: 1412-7.
    CrossrefPubMedGoogle Scholar
  • 57 Wieczorek I, Ludlam CA, Fox KA. Tissue-type plasminogen activator and plasminogen activator inhibitor activities as predictors of adverse events in unstable angina. Am J Cardiol 1994; 74: 424-9.
    CrossrefPubMedGoogle Scholar
  • 58 Smith FB, Rumley A, Lee AJ, Leng GC, Fowkes FG, Lowe GD. Haemostatic factors and prediction of ischaemic heart disease and stroke in claudicants. Br J Haematol 1998; 100: 758-63.
    CrossrefPubMedGoogle Scholar
  • 59 Soeki T, Tamura Y, Shinohara H, Tanaka H, Bando K, Yui Y, Fukuda N. Fibrinolytic factors, serum lipid and C-reactive protein predicting cardiac events in Japanese patients with coronary atherosclerotic lesions. Jpn Circ J 1999; 63: 976-80.
    CrossrefPubMedGoogle Scholar
  • 60 Held C, Hjemdahl P, Rehnqvist N, Wallen NH, Bjorkander I, Eriksson SV, Forslund L, Wiman B. Fibrinolytic variables and cardiovascular prognosis in patients with stable angina pectoris treated with verapamil or metoprolol. Results from the Angina Prognosis study in Stockholm. Circulation 1997; 95: 2380-6.
    CrossrefPubMedGoogle Scholar
  • 61 Bavenholm P, de Faire U, Landou C, Efendic S, Nilsson J, Wiman B, Hamsten A. Progression of coronary artery disease in young male post-infarction patients is linked to disturbances of carbohydrate and lipoprotein metabolism and to impaired fibrinolytic function. Eur Heart J 1998; 19: 402-10.
    CrossrefPubMedGoogle Scholar
  • 62 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: 2236-40.
    CrossrefPubMedGoogle Scholar
  • 63 MacCallum PK, Cooper JA, Martin J, Howarth DJ, Meade TW, Miller GJ. Haemostatic and lipid determinants of prothrombin fragment F1.2 and D-dimer in plasma. Thromb Haemost 2000; 83: 421-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 64 Nesheim ME. TAFI. Fibrinolysis & Proteolysis 1999; 13: 72-7.
    CrossrefPubMedGoogle Scholar
  • 65 van der Bom JG, de Knijff P, Haverkate F, Bots ML, Meijer P, de Jong PT, Hofman A, Kluft C, Grobbee DE. Tissue plasminogen activator and risk of myocardial infarction. The Rotterdam Study. Circulation 1997; 95: 2623-7.
    CrossrefPubMedGoogle Scholar
  • 66 Steeds R, Adams M, Smith P, Channer K, Samani NJ. Distribution of tissue plasminogen activator insertion/deletion polymorphism in myocardial infarction and control subjects. Thromb Haemost 1998; 79: 980-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 67 Ridker PM, Baker MT, Hennekens CH, Stampfer MJ, Vaughan DE. Alu-repeat polymorphism in the gene coding for tissue-type plasminogen activator (t-PA) and risks of myocardial infarction among middle-aged men. Arterioscler Thromb Vasc Biology 1997; 17: 1687-90.
    PubMedGoogle Scholar
  • 68 Iacoviello L, Di Castelnuovo A, De Knijff P, D’Orazio A, Amore C, Kluft C, Donati MB. Alu-repeat polymorphism in the tissue-type plasminogen activator (t-PA) gene, t-PA levels and risk of familial myocardial infarction (MI). Fibrinolysis 1996; 10 (Suppl. 02) 13-16.
    PubMedGoogle Scholar
  • 69 Eriksson P, Kallin B, van’t Hooft FM, Bavenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851-5.
    CrossrefPubMedGoogle Scholar
  • 70 Iacoviello L. The 4G/5G polymorphism of PAI-1 promoter gene and the risk of myocardial infarction: A meta-analysis [Letter]. Thromb Haemost 1998; 80: 1029-30.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 71 Gardemann A, Lohre J, Katz N, Tillmanns H, Hehrlein FW, Haberbosch W. The 4G4G genotype of the plasminogen activator inhibitor 4G/5G gene polymorphism is associated with coronary atherosclerosis in patients at high risk for this disease. Thromb Haemost 1999; 82: 1121-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 72 Roest M, van der Schouw YT, Banga JD, Tempelman MJ, de Groot PG, Sixma JJ, Grobbee DE. Plasminogen activator inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in older women. Circulation 2000; 101: 67-70.
    CrossrefPubMedGoogle Scholar
  • 73 Doggen CJM, Bertina RM, Cats VM, Reitsma PH, Rosendaal FR. The 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is not associated with myocardial infarction. Thromb Haemost 1999; 82: 115-20.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 74 Iwai N, Shimoike H, Nakamura Y, Tamaki S, Kinoshita M. The 4G/5G polymorphism of the plasminogen activator inhibitor gene is associated with the time course of progression to acute coronary syndromes. Atherosclerosis 1998; 136: 109-14.
    CrossrefPubMedGoogle Scholar
  • 75 Catto AJ, Carter AM, Stickland M, Bamford JM, Davies JA, Grant PJ. Plasminogen activator inhibitor-1 (PAI-1) 4G/5G promoter polymorphism and levels in subjects with cerebrovascular disease. Thromb Haemost 1997; 77: 730-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 76 Lee AJ, Fowkes FG, Lowe GD, Connor JM, Rumley A. Fibrinogen, factor VII and PAI-1 genotypes and the risk of coronary and peripheral atherosclerosis: Edinburgh Artery Study. Thromb Haemost 1999; 81: 553-60.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 77 Medical Research Council’s General Practice Research Framework.. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 351: 233-41.
    CrossrefPubMedGoogle Scholar
  • 78 Behar S. Lowering fibrinogen levels: clinical update. BIP Study Group. Bezafibrate Infarction Prevention. Blood Coagul Fibrinolysis 1999; 10 (Suppl. 01) S41-3.
    PubMedGoogle Scholar