Haemostatic and Lipid Determinants of Prothrombin Fragment F1.2 and D-dimer in Plasma

Peter K. MacCalum; Jackie A. Cooper; Janet Martin; David J. Howarth; Thomas W. Meade; George J. Miller

doi:10.1055/s-0037-1613831

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2000; 83(03): 421-426
DOI: 10.1055/s-0037-1613831

Review Article

Schattauer GmbH

Haemostatic and Lipid Determinants of Prothrombin Fragment F1.2 and D-dimer in Plasma

Authors

Peter K. MacCalum

¹From the MRC Epidemiology and Medical C are Unit, Wolfson Institute of Preventive Medicine, St Bartholomew‘s and the Royal London School of Medicine, London, UK
Jackie A. Cooper

¹From the MRC Epidemiology and Medical C are Unit, Wolfson Institute of Preventive Medicine, St Bartholomew‘s and the Royal London School of Medicine, London, UK
Janet Martin

¹From the MRC Epidemiology and Medical C are Unit, Wolfson Institute of Preventive Medicine, St Bartholomew‘s and the Royal London School of Medicine, London, UK
David J. Howarth

¹From the MRC Epidemiology and Medical C are Unit, Wolfson Institute of Preventive Medicine, St Bartholomew‘s and the Royal London School of Medicine, London, UK
Thomas W. Meade

¹From the MRC Epidemiology and Medical C are Unit, Wolfson Institute of Preventive Medicine, St Bartholomew‘s and the Royal London School of Medicine, London, UK
George J. Miller

¹From the MRC Epidemiology and Medical C are Unit, Wolfson Institute of Preventive Medicine, St Bartholomew‘s and the Royal London School of Medicine, London, UK

Abstract

Summary

The determinants of plasma levels of prothrombin fragment F1.2 (F1.2) and D-dimer in different populations are unclear and this may complicate their interpretation as predictors of thrombotic risk, particularly in the case of D-dimer. We therefore measured F1.2 and D-dimer levels together with a number of other haemostatic and lipid variables in a cross-sectional community-based study of 150 healthy adults (73 male, 77 female), age range 23-80 years, identified from the list of a general practice by stratified random sampling within sex and decade of age. Plasma F1.2 was significantly higher in females than males and was independently and positively associated with age, factor VII activity (FVIIc) and C1 inhibitor, and inversely associated with high density lipoprotein (HDL) cholesterol. Plasma D-dimer showed a quadratic association with age (p <0.0001). In those ≤55 years D-dimer was inversely associated with dilute clot lysis time (DCLT) and activated protein C (APC) ratio. In those >55 years it was significantly higher in females than males and associated positively with age, fibrinogen and, in males, activated factor XII (FXIIa). In a multiple-linear model which combined both age groups, F1.2 and D-dimer were independently associated with each other (r = 0.22, p = 0.03). Thus, thrombin generation and fibrin turnover/fibrinolysis are associated in healthy subjects. HDL cholesterol (inversely) and FVIIc are associated with basal thrombin generation (i.e. F1.2). Determinants of D-dimer differ according to age and interpretation of the biological significance of D-dimer levels in epidemiological studies may therefore not be straightforward.

Keywords

Haemostatic system - coagulation - fibrinolysis - prothrombin fragment F1.2 - D-dimer

Full Text

References

References
1 Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic state in humans: Insights gained from studies using markers of hemostatic system activation. Blood 1987; 70: 343-50.
2 Bauer KA, Broekmans AW, Bertina RM, Conard J, Horellou M-H, Samama MM, Rosenberg RD. Hemostatic enzyme generation in the blood of patients with hereditary protein C deficiency. Blood 1988; 71: 1418-26.
3 Merlini PA, Bauer KA, Oltrona L, Ardissino D, Cattaneo M, Belli C, Mannucci PM, Rosenberg RD. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994; 90: 61-8.
4 Bauer KA, Weiss LM, Sparrow D, Vokonas PS, Rosenberg RD. Aging-associated changes in indices of thrombin generation and protein C activation in humans. Normative Aging Study. J Clin Invest 1987; 80: 1527-34.
5 Miller GJ, Wilkes HC, Meade TW, Bauer KA, Barzegar S, Rosenberg RD. Haemostatic changes that constitute the hypercoagulable state. Lancet 1991; 338: 1079.
6 Cadroy Y, Pierrejean D, Fontan B, Sie P, Boneu B. Influence of aging on the activity of the hemostatic system: prothrombin fragment 1+2, thrombinantithrombin III complexes and D-dimers in 80 healthy subjects with age ranging from 20 to 94 years. Nouv Rev Fr Hematol 1992; 34: 43-6.
7 Hursting MJ, Stead AG, Crout FV, Horvath BZ, Moore BM. Effects of age, race, sex, and smoking on prothrombin fragment F1.2 in a healthy population. Clin Chem 1993; 39: 683-6.
8 Mari D, Mannucci PM, Coppola R, Bottasso B, Bauer KA, Rosenberg RD. Hypercoagulability in centenarians: the paradox of successful aging. Blood 1995; 85: 3144-9.
9 Cushman M, Psaty BM, Macy E, Bovill EG, Cornell ES, Kuller LH, Tracy RP. Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease. Arterioscler Thromb Vasc Biol 1996; 16: 1163-9.
10 Miller GJ, Bauer KA, Barzegar S, Cooper JA, Rosenberg RD. Increased activation of the haemostatic system in men at high risk of fatal coronary heart disease. Thromb Haemost 1996; 75: 767-71.
11 Lowe GDO, Rumley A, Woodward M, Morrison CE, Phillippou 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: 775-84.
12 Miller GJ, Bauer KA, Cooper JA, Rosenberg RD. Activation of the coagulant pathway in cigarette smokers. Thromb Haemost 1998; 79: 549-53.
13 Gouin-Thibault I, Dewar L, Craven S, Kulczycky M, Wun T-C, Ofosu FA. Probable regulation of factor VIIa-tissue factor and prothrombinase by factor Xa-TFPI and TFPI in vivo. Br J Haematol 1996; 95: 738-46.
14 Gaffney PJ. F. D. P. Lancet 1972; ii: 1422.
15 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.
16 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: 129-33.
17 Cushman M, Lemaitre RN, Kuller LH, Psaty BM, Macy EM, Sharett AR, Tracy RP. Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1999; 19: 493-8.
18 Fowkes FGR, Lowe GDO, Housley E, Rattray A, Rumley A, Elton RA, MacGregor IR, Dawes J. Cross-linked fibrin degradation products, progression of peripheral arterial disease, and risk of coronary heart disease. Lancet 1993; 342: 84-6.
19 Cortellaro M, Cofrancesco E, Boschetti C, Mussoni L, Donati MB, Cardillo M, Catalano M, Gabrielli L, Lombardi B, Specchia G, Tavazzi L, Tremoli E, Pozzoli E, Turri M. for the PLAT Group. 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.
20 Lee AJ, Fowkes FGR, Lowe GDO, Rumley A. Determinants of fibrin D-dimer in the Edinburgh Artery Study. Arterioscler Thromb Vasc Biol 1995; 15: 1094-7.
21 Lee AJ, Fowkes FGR, Lowe GDO, Rumley A. Fibrin D-dimer, haemostatic factors and peripheral arterial disease. Thromb Haemost 1995; 74: 828-32.
22 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.
23 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.
24 Lip GYH, Lowe GDO. Fibrin D-dimer: a useful clinical marker of thrombogenesis?. Clin Sci 1995; 89: 205-14.
25 MacCallum PK, Cooper JA, Howarth DJ, Meade TW, Miller GJ. Sex differences in the determinants of fibrinolytic activity. Thromb Haemost 1998; 79: 587-90.
26 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-46.
27 Miller GJ, Stirling Y, Esnouf MP, Heinrich J, van de Loo J, Kienast J, Wu KK, Morrissey JH, Meade TW, Martin JC, Imeson JD, Cooper JA, Finch A. Factor VII-deficient substrate plasmas depleted of protein C raise the sensitivity of the factor VII bio-assay to activated factor VII: an international study. Thromb Haemost 1994; 71: 38-48.
28 Mannucci PM, Bauer KA, Santagostino E, Faioni E, Barzegar S, Coppola R, Rosenberg RD. Activation of the coagulation cascade after infusion of a factor XI concentrate in congenitally deficient patients. Blood 1994; 84: 1314-9.
29 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: 527-33.
30 Lip GYH, Lip PL, Zarifis J, Watson RDS, Bareford D, Lowe GDO, Beevers DG. Fibrin D-dimer and 13-thromboglobulin as markers of thrombogenesis and platelet activation in atrial fibrillation. Effects of introducing ultra-lowdose warfarin and aspirin. Circulation 1996; 94: 425-31.
31 Uttley WS, Allan AGE, Cash JD. Fibrin/fibrinogen degradation products in sera of normal infants and children. Arch Dis Child 1969; 44: 761-4.
32 Nieuwenhuizen W. A reference material for harmonisation of D-dimer assays. Thromb Haemost 1997; 77: 1031-3.
33 Bajzar L, Nesheim ME, Tracy PB. The profibrinolytic effect of activated protein C in clots formed from plasma is TAFI-dependent. Blood 1996; 88: 2093-100.
34 Ceriello A, Pirisi M, Giacomello R, Stel G, Falleti E, Motz E, Lizzio S, Gonano F, Bartoli E. Fibrinogen plasma levels as a marker of thrombin activation: new insights on the role of fibrinogen as a cardiovascular risk factor. Thromb Haemost 1994; 71: 593-5.
35 Giansante C, Fiotti N, Cattin L, Da Col PG, Calabrese S. Fibrinogen, D-dimer and thrombin-antithrombin complexes in a random population sample: relationships with other cardiovascular risk factors. Thromb Haemost 1994; 71: 581-6.
36 Franks JJ, Kirsch RE, ’C Frith LO, Purves LR, Franks WT, Franks JA, Mason P, Saunders SJ. Effect of fibrinogenolytic products D and E on fibrinogen and albumin synthesis in the rat. J Clin Invest 1981; 67: 575-80.
37 Mosesson MW, Siebenlist KR, Voskuilen M, Nieuwenhuizen W. Evaluation of the factors contributing to fibrin-dependent plasminogen activation. Thromb Haemost 1998; 79: 796-801.
38 Miller GJ, Esnouf MP, Burgess AI, Cooper JA, Mitchell JP. Risk of coronary heart disease and activation of factor XII in middle-aged men. Arterioscler Thromb Vasc Biol 1997; 17: 2103-6.
39 Kohler HP, Carter AM, Stickland MH, Grant PJ. Levels of activated FXII in survivors of myocardial infarction – association with circulating risk factors and extent of coronary artery disease. Thromb Haemost 1998; 79: 14-8.
40 Mitropoulos KA, Esnouf MP. The prothrombin activation peptide regulates synthesis of the vitamin K-dependent proteins in the rabbit. Thromb Res 1990; 57: 541-9.
41 Woodward M, Lowe GDO, Rumley A, Tunstall-Pedoe H, Philippou H, Lane DA, 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: 785-97.
42 Gordon DJ, Rifkind BM. High-density lipoprotein. – the clinical implications of recent studies.. N Engl J Med 1989; 321: 1311-6.
43 Griffin JH, Kojima K, Banka CL, Curtiss LK, Fernandez JA. High-density lipoprotein enhancement of anticoagulant activities of plasma protein S and activated protein C. J Clin Invest 1999; 103: 219-27.
44 Phillips AN, Davey GSmith. Bias in relative odds estimation owing to imprecise measurement of correlated exposures. Stat Med 1992; 11: 953-61.
45 Moyer MP, Tracy RP, Tracy PB, van’t Veer C, Sparks CE, Mann KG. Plasma lipoproteins support prothrombinase and other procoagulant enzymatic complexes. Arterioscler Thromb Vasc Biol 1998; 18: 458-65.
46 Hoffman CJ, Lawson WE, Miller RH, Hultin MB. Correlation of vitamin K-dependent clotting factors with cholesterol and triglycerides in healthy young adults. Arterioscler Thromb 1994; 14: 1737-40.
47 Wuillemin WA, Minnema M, Meijers JCM, Roem D, Eerenberg AJM, Nuijens JH, ten Cate H, Hack CE. Inactivation of factor XIa in human plasma assessed by measuring factor XIa-protease inhibitor complexes: major role for C1-inhibitor. Blood 1995; 85: 1517-26.
48 Wuillemin WA, Hack CE, Bleeker WK, Biemond BJ, Levi M, ten Cate H. Inactivation of factor XIa in vivo: studies in chimpanzees and in humans. Thromb Haemost 1996; 76: 549-55.
49 Cugno M, Cicardi M, Bottasso B, Coppola R, Paonessa R, Mannucci PM, Agostoni A. Activation of the coagulation cascade in C1-inhibitor deficiencies. Blood 1997; 89: 3213-8.
50 Gailani D, Broze Jr GJ. Factor XI activation in a revised model of blood coagulation. Science 1991; 253: 909-12.
51 von dem Borne PAK, Mosnier LO, Tans G, Meijers JCM, Bouma BN. Factor XI activation by meizothrombin: stimulation by phospholipid vesicles containing both phosphatidylserine and phosphatidylethanolamine. Thromb Haemost 1997; 78: 834-9.
52 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: 82-6.
53 Johansen LG, Gram J, Kluft C, Jespersen J. Chronobiology of coronary risk markers in Greenland Eskimos: a comparative study with Caucasians residing in the same Arctic area. Chronobiol Int 1991; 08: 352-60.
54 Jafri SM, VanRollins M, Ozawa T, Mammen EF, Goldberg AD, Goldstein S. Circadian variation in platelet function in healthy volunteers. Am J Cardiol 1992; 69: 951-4.