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Effects of age and vascular disease on coagulation and fibrinolysis turnover products
Fv
(1992)6, Supp: 3,25-26
@ Longman Group UK Ltd 1992
Effects of Age and Vascular Disease on Coagulation and Fibrinolysis Turnover Products
G.D.O. Lowe
SUMMARY
Both increasing age and vascular diseases are associated with increases in coagulation and fihrinolysis turnover products. In part, increases in turnover products may reflect increases in coagulation factor concentrations. The increases in coagulation activity may be “balanced” to some extent by age-related increases in fibrinolytic activity. An imbalance between coagulation and fibrinolysis is associated with several major risk factors and vascular disorders: the effect of age on such an imbalance remains to be determined.
KEYWORDS.
Blood coagulation.
WHY STUDY TURNOVER
Fibrinolysis.
Age. Vascular
PRODUCTS?
products of coagulation and fibrinolysis reflect the action of these systems in vivo: this is their prime attraction. Coagulation times, factors and inhibitors only reflect potential: as do clot lysis times, fibrin plate lysis areas, fibrinolytic factors and inhibitors. Potential as measured on the laboratory bench can be misleading: for example, the “fibrinolytic shutdown” suggested by clot lysis times in samples taken after trauma or surgery does not appear to occur in vivo, because increased levels of fibrin(ogen) degradation products are observed simultaneously.
Turnover
diseases
levels are a true reflection of plasma levels): such approaches minimise chance venepuncture activation and can be used to measure activity over a time period which may be more representative than single measurements. The interaction of products with fibrinogen or fibrin may be a problem, e.g. failure to completely remove fibrinogen by bentonite precipitation when preparing plasma samples for FpA measurement; or formation (or loss in the fibrin clot) of fibrin(ogen) degradation products when serum samples are prepared for measurement.3 Finally, sampling an arm vein distant from the active site of coagulation or fibrinolysis (e.g. a distant thrombus) may reduce the sensitivity of activation product measurements.
WHAT ARE THE PROBLEMS?
Unfortunately, there are several potential problems with the interpretation of turnover product levels.tS3 Many products have short half-lives, hence a single blood sample, which may be taken at a peak or a trough of activity, may not be representative of “median” activity. In this respect, turnover products appear more labile than levels of clotting or lysis times, factors or inhibitors. Some products, notably fibrinopeptide A (FpA), are sensitive to CYriw generation during blood sampling, giving spurious high results.2 Approaches to these problems include taking several blood samples over a period of time (rarely done!) or collecting urine samples over a period of time (if urine University Department of Medicine, Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, United Kingdom
COAGULATION
TURNOVER
PRODUCTS
Despite these problems, several coagulation turnover products have been associated with both age and vascular diseases. Fibrinopeptide A, a measure of thrombin activity upon fibrinogen, has been found to increase with age in several studies.4-61n one of these studies,’ evidence for thrombin generation increasing with age was supported by increases with age in prothrombin fragment F1+2 (split from prothrombin upon its activation to thrombin) and in protein C activation peptide (split from protein C by the thrombinthrombo-modulin complex). The increase in fibrinopeptide A with age was observed in the only epidemiological study reported to dateP even within the narrow age range of 35-54 years.
26 Effects of Age and Vascular Disease on Coagulation and Fibrinolysis Turnover Products
What causes this increase in coagulation with age? One possibility is increased platelet activation with age, as measured by plasma levels of the a-granule release product, fi-thromboglobulin.“4 Another possibility is increased levels of coagulation factors, including fibrinogen and factor VII, with age.6*71nan epidemiological study, FpA levels correlated with factor VII, fibrinogen, and plasma viscosity which is partly determined by fibrinogen levels and which also increases with age.6 Several major cardiovascular risk factors which increase with age (blood pressure, obesity, serum cholesterol and triglyceride) were also associated with FpA levels in this study,6 and might promote increased thrombin generation by increasing coagulation factor levels or by other mechanisms (e.g. by increasing arterial injury). These increases in thrombin generation with age are likely to be relevant to the increasing incidence of vascular diseases with age, because premature elevations in these products have been reported in persons with vascular diseases.‘~2~4*5,8
FIBRINOLYSIS TURNOVER PRODUCTS Because one of the body’s responses to coagulation activation and fibrin formation is activation of the fibrinolytic system, it is interesting to relate coagulation activation products to fibrinolytic activation products. Nosse19 suggested that one approach might be to measure the ratio of thrombin action on fibrinogen (FpA levels) to plasmin action on librin(ogen) (levels of B&-43or BP,sazpeptide levels). In an epidemiological study of men aged 35-54 years, this ratio did not correlate significantly with age, unlike FpA levels;6 however a larger study across a wider age range would be required to establish whether or not there is an increase in this ratio of coagulation activation to fibrinolytic activation with age. Such an imbalance might favour thrombosis and atherosclerosis, as suggested by Astrup,” and in the same study correlated with major cardiovascular risk factors, factor VII, fibrinogen and plasma visc0sity.b We have also observed such an imbalance in diabetes, acute and chronic coronary artery disease, and acute stroke. Recently there has been increasing interest in measurement of librin(ogen) degradation products, following development of specific and sensitive immunoassays which can be performed in plasma samples.3 Such degradation products reflect activation of both coagulation and fibrinolysis, and cannot be used to assess the relative activity of these two opposing systems. However cross-linked Gbrin degradation products (measured as D-dimer antigen) have attracted particular interest, as they appear to relate lo the extent
of both venous thromboembolismtt and peripheral We have recently found in an arterial disease.12 epidemiological study of 800 persons that plasma Ddimer levels increase with age, almost doubling between age 25 and 75 years (mean 50 to 90 ng/ml); and that Ddimer levels are increased in persons with coronary or peripheral arterial disease (unpublished observations). D-dimer levels also correlated with smoking habit, fibrinogen levels, and with plasma antigen levels of two endothelial markers: von Willebrand’ factor and tissue plasminogen activator; all of which increase with both age and vascular disease. It appears that D-dimer levels may reflect vascular damage, and may be a marker of arterial fibrin turnover. Further studies are required to explore this possibility.
REFERENCES 1. Kaplan K L, Owen J 1983 Radioimmunoassays of platelet alpha granule proteins. In: Harker L A, Zimmerman T S (eds), Measurement of Platelet Function. Churchill Livingstone, Edinburgh, 115-125 2. Owen J 1987 On the quantitative interpretation of plasma fibrinopeptide levels. In: Lowe G D 0, Douglas J T, Forbes C D, Henschen A (eds), Fibrinogen 2. Biochemistry, Physiology and Clinical Relevance. Excerpta Medica, Amsterdam, 237-240 3. Nieuwenhuizen W 1991 The formation, measurement and clinical value of fibrinogen derivatives. In: Thomson J M (ed), Blood Coagulation and Haemostasis: A Practical Guide. Churchill Livingstone, Edinburgh, 151-175 4. Stewart M E, Douglas J T, Lowe G D 0, Prentice C R M. Forbes C D 1983 Prognostic value of beta-thromboglobulin in patients with transient cerebral ischaemia. Lancet ii: 479-482 5. Bauer KK A, Weiss L M, Sparrow D, Vokoras P S, Rosenberg R D 1987 Ageing-related changes in indices of thmmbin generation and protein C activation in humans. Normative ageing study. J Clin Invest 80: 1527-1534 6. Lowe G D 0, Wood D A, Douglas J T, Riemersma R A, Maclntyre C C A, Takase T, Tuddenham E G D, Forbes C D, Elton Ii A. Oliver M F 1991 Relationships of plasma viscosity, coagulation and fibrinolysis to coronary risk factors and angina. Thromb Haemostas 65: 339-343 7. Ogston D 1983 The physiology of haemostasis. Croom Helm, London, 254 8. Boisclair M D, Ireland II, Lane D A 1990 Assessment of hypercoagulable states by measurement of activation fragments and peptides. Blood Reviews 4: 255-40 9. Nossel H L 1981 Relative proteolysis of the fibrinogen Bfichain by thrombin and plasmin as a determinant of thrombosis. Nature 291: X5-167 10. Astrup T 1956 Fibrinolysis in the organism. Blood 11: 781-806 11. Rowbotham B J, Carroll P, Whitaker A N, Bunce I H, Cobcroft R G, Elms M J, Masci P P, Bundesen P G, Rylatt D B, Webber A J 1987 Measurement of crosslinked fibrin derivatives - use in the diagnosis of venous thrombosis. Thromb Haemostas 57: 59-61 12. Lowe G D 0, Douglas J T, Zahrani H, Pollock J G, Smith W C S, Tunstall-Pedoe H 1988 Plasma D-dimer antigen in chronic peripheral arterial disease and in a population study. Fibrinolysis 2, supp 1: 37
(1992)6, Supp: 3,25-26
@ Longman Group UK Ltd 1992
Effects of Age and Vascular Disease on Coagulation and Fibrinolysis Turnover Products
G.D.O. Lowe
SUMMARY
Both increasing age and vascular diseases are associated with increases in coagulation and fihrinolysis turnover products. In part, increases in turnover products may reflect increases in coagulation factor concentrations. The increases in coagulation activity may be “balanced” to some extent by age-related increases in fibrinolytic activity. An imbalance between coagulation and fibrinolysis is associated with several major risk factors and vascular disorders: the effect of age on such an imbalance remains to be determined.
KEYWORDS.
Blood coagulation.
WHY STUDY TURNOVER
Fibrinolysis.
Age. Vascular
PRODUCTS?
products of coagulation and fibrinolysis reflect the action of these systems in vivo: this is their prime attraction. Coagulation times, factors and inhibitors only reflect potential: as do clot lysis times, fibrin plate lysis areas, fibrinolytic factors and inhibitors. Potential as measured on the laboratory bench can be misleading: for example, the “fibrinolytic shutdown” suggested by clot lysis times in samples taken after trauma or surgery does not appear to occur in vivo, because increased levels of fibrin(ogen) degradation products are observed simultaneously.
Turnover
diseases
levels are a true reflection of plasma levels): such approaches minimise chance venepuncture activation and can be used to measure activity over a time period which may be more representative than single measurements. The interaction of products with fibrinogen or fibrin may be a problem, e.g. failure to completely remove fibrinogen by bentonite precipitation when preparing plasma samples for FpA measurement; or formation (or loss in the fibrin clot) of fibrin(ogen) degradation products when serum samples are prepared for measurement.3 Finally, sampling an arm vein distant from the active site of coagulation or fibrinolysis (e.g. a distant thrombus) may reduce the sensitivity of activation product measurements.
WHAT ARE THE PROBLEMS?
Unfortunately, there are several potential problems with the interpretation of turnover product levels.tS3 Many products have short half-lives, hence a single blood sample, which may be taken at a peak or a trough of activity, may not be representative of “median” activity. In this respect, turnover products appear more labile than levels of clotting or lysis times, factors or inhibitors. Some products, notably fibrinopeptide A (FpA), are sensitive to CYriw generation during blood sampling, giving spurious high results.2 Approaches to these problems include taking several blood samples over a period of time (rarely done!) or collecting urine samples over a period of time (if urine University Department of Medicine, Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, United Kingdom
COAGULATION
TURNOVER
PRODUCTS
Despite these problems, several coagulation turnover products have been associated with both age and vascular diseases. Fibrinopeptide A, a measure of thrombin activity upon fibrinogen, has been found to increase with age in several studies.4-61n one of these studies,’ evidence for thrombin generation increasing with age was supported by increases with age in prothrombin fragment F1+2 (split from prothrombin upon its activation to thrombin) and in protein C activation peptide (split from protein C by the thrombinthrombo-modulin complex). The increase in fibrinopeptide A with age was observed in the only epidemiological study reported to dateP even within the narrow age range of 35-54 years.
26 Effects of Age and Vascular Disease on Coagulation and Fibrinolysis Turnover Products
What causes this increase in coagulation with age? One possibility is increased platelet activation with age, as measured by plasma levels of the a-granule release product, fi-thromboglobulin.“4 Another possibility is increased levels of coagulation factors, including fibrinogen and factor VII, with age.6*71nan epidemiological study, FpA levels correlated with factor VII, fibrinogen, and plasma viscosity which is partly determined by fibrinogen levels and which also increases with age.6 Several major cardiovascular risk factors which increase with age (blood pressure, obesity, serum cholesterol and triglyceride) were also associated with FpA levels in this study,6 and might promote increased thrombin generation by increasing coagulation factor levels or by other mechanisms (e.g. by increasing arterial injury). These increases in thrombin generation with age are likely to be relevant to the increasing incidence of vascular diseases with age, because premature elevations in these products have been reported in persons with vascular diseases.‘~2~4*5,8
FIBRINOLYSIS TURNOVER PRODUCTS Because one of the body’s responses to coagulation activation and fibrin formation is activation of the fibrinolytic system, it is interesting to relate coagulation activation products to fibrinolytic activation products. Nosse19 suggested that one approach might be to measure the ratio of thrombin action on fibrinogen (FpA levels) to plasmin action on librin(ogen) (levels of B&-43or BP,sazpeptide levels). In an epidemiological study of men aged 35-54 years, this ratio did not correlate significantly with age, unlike FpA levels;6 however a larger study across a wider age range would be required to establish whether or not there is an increase in this ratio of coagulation activation to fibrinolytic activation with age. Such an imbalance might favour thrombosis and atherosclerosis, as suggested by Astrup,” and in the same study correlated with major cardiovascular risk factors, factor VII, fibrinogen and plasma visc0sity.b We have also observed such an imbalance in diabetes, acute and chronic coronary artery disease, and acute stroke. Recently there has been increasing interest in measurement of librin(ogen) degradation products, following development of specific and sensitive immunoassays which can be performed in plasma samples.3 Such degradation products reflect activation of both coagulation and fibrinolysis, and cannot be used to assess the relative activity of these two opposing systems. However cross-linked Gbrin degradation products (measured as D-dimer antigen) have attracted particular interest, as they appear to relate lo the extent
of both venous thromboembolismtt and peripheral We have recently found in an arterial disease.12 epidemiological study of 800 persons that plasma Ddimer levels increase with age, almost doubling between age 25 and 75 years (mean 50 to 90 ng/ml); and that Ddimer levels are increased in persons with coronary or peripheral arterial disease (unpublished observations). D-dimer levels also correlated with smoking habit, fibrinogen levels, and with plasma antigen levels of two endothelial markers: von Willebrand’ factor and tissue plasminogen activator; all of which increase with both age and vascular disease. It appears that D-dimer levels may reflect vascular damage, and may be a marker of arterial fibrin turnover. Further studies are required to explore this possibility.
REFERENCES 1. Kaplan K L, Owen J 1983 Radioimmunoassays of platelet alpha granule proteins. In: Harker L A, Zimmerman T S (eds), Measurement of Platelet Function. Churchill Livingstone, Edinburgh, 115-125 2. Owen J 1987 On the quantitative interpretation of plasma fibrinopeptide levels. In: Lowe G D 0, Douglas J T, Forbes C D, Henschen A (eds), Fibrinogen 2. Biochemistry, Physiology and Clinical Relevance. Excerpta Medica, Amsterdam, 237-240 3. Nieuwenhuizen W 1991 The formation, measurement and clinical value of fibrinogen derivatives. In: Thomson J M (ed), Blood Coagulation and Haemostasis: A Practical Guide. Churchill Livingstone, Edinburgh, 151-175 4. Stewart M E, Douglas J T, Lowe G D 0, Prentice C R M. Forbes C D 1983 Prognostic value of beta-thromboglobulin in patients with transient cerebral ischaemia. Lancet ii: 479-482 5. Bauer KK A, Weiss L M, Sparrow D, Vokoras P S, Rosenberg R D 1987 Ageing-related changes in indices of thmmbin generation and protein C activation in humans. Normative ageing study. J Clin Invest 80: 1527-1534 6. Lowe G D 0, Wood D A, Douglas J T, Riemersma R A, Maclntyre C C A, Takase T, Tuddenham E G D, Forbes C D, Elton Ii A. Oliver M F 1991 Relationships of plasma viscosity, coagulation and fibrinolysis to coronary risk factors and angina. Thromb Haemostas 65: 339-343 7. Ogston D 1983 The physiology of haemostasis. Croom Helm, London, 254 8. Boisclair M D, Ireland II, Lane D A 1990 Assessment of hypercoagulable states by measurement of activation fragments and peptides. Blood Reviews 4: 255-40 9. Nossel H L 1981 Relative proteolysis of the fibrinogen Bfichain by thrombin and plasmin as a determinant of thrombosis. Nature 291: X5-167 10. Astrup T 1956 Fibrinolysis in the organism. Blood 11: 781-806 11. Rowbotham B J, Carroll P, Whitaker A N, Bunce I H, Cobcroft R G, Elms M J, Masci P P, Bundesen P G, Rylatt D B, Webber A J 1987 Measurement of crosslinked fibrin derivatives - use in the diagnosis of venous thrombosis. Thromb Haemostas 57: 59-61 12. Lowe G D 0, Douglas J T, Zahrani H, Pollock J G, Smith W C S, Tunstall-Pedoe H 1988 Plasma D-dimer antigen in chronic peripheral arterial disease and in a population study. Fibrinolysis 2, supp 1: 37