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. 1987 Dec;80(6):1527–1534. doi: 10.1172/JCI113238

Aging-associated changes in indices of thrombin generation and protein C activation in humans. Normative Aging Study.

K A Bauer 1, L M Weiss 1, D Sparrow 1, P S Vokonas 1, R D Rosenberg 1
PMCID: PMC442420  PMID: 2824564

Abstract

In view of the known association of vascular disease with increasing age, we have conducted an analysis of hemostatic system activity with respect to perturbations induced by aging phenomena. We have utilized an immunochemical assay for prothrombin fragment F1 + 2 to quantify Factor Xa activity upon prothrombin in the plasma of 199 healthy males between the ages of 42 and 80. The levels of F1 + 2 in this population generally increased as a function of age (P less than 0.0001). The metabolic behavior of this marker was determined in 10 individuals greater than 65 yr of age with varying levels of F1 + 2, which ranged from 1.28 to 5.85 nM. The elevations in the concentration of this component were not due to diminished clearance of the fragment. Radio-immunoassays for fibrinopeptide A (FPA) and the protein C activation peptide (PCP) were subsequently employed to measure thrombin activity upon fibrinogen and thrombin-thrombomodulin activity upon protein C, respectively, in 82 members of this population ranging in age from 42 to 80. Significant positive correlations were again observed between increasing age and the level of F1 + 2 (P less than 0.0001) as well as FPA (P less than 0.01) and PCP (P less than 0.002). The results of this cross-sectional study indicate that many apparently normal males of increasing age with normal immunologic levels of antithrombin III and protein C exhibit a biochemical defect that denotes the presence of an acquired prethrombotic state.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aronson D. L., Stevan L., Ball A. P., Franza B. R., Jr, Finlayson J. S. Generation of the combined prothrombin activation peptide (F1-2) during the clotting of blood and plasma. J Clin Invest. 1977 Dec;60(6):1410–1418. doi: 10.1172/JCI108902. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bauer K. A., Ashenhurst J. B., Chediak J., Rosenberg R. D. Antithrombin "Chicago": a functionally abnormal molecule with increased heparin affinity causing familial thrombophilia. Blood. 1983 Dec;62(6):1242–1250. [PubMed] [Google Scholar]
  3. Bauer K. A., Goodman T. L., Kass B. L., Rosenberg R. D. Elevated factor Xa activity in the blood of asymptomatic patients with congenital antithrombin deficiency. J Clin Invest. 1985 Aug;76(2):826–836. doi: 10.1172/JCI112040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bauer K. A., Kass B. L., Beeler D. L., Rosenberg R. D. Detection of protein C activation in humans. J Clin Invest. 1984 Dec;74(6):2033–2041. doi: 10.1172/JCI111626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bertina R. M., Westhoek-Kuipers M. E., Alderkamp G. H. The inhibitor of prothrombin conversion in plasma of patients on oral anticoagulant treatment. Thromb Haemost. 1981 Jun 30;45(3):237–241. [PubMed] [Google Scholar]
  6. Bidet J. M., Ferriere J. P., Besse G., Chollet P., Gaillard G., Plagne R. Evaluation of beta thromboglobulin levels in cancer patients: effects of antitumor chemotherapy. Thromb Res. 1980 Aug 1;19(3):429–433. doi: 10.1016/0049-3848(80)90272-8. [DOI] [PubMed] [Google Scholar]
  7. Bolton A. E., Ludlam C. A., Pepper D. S., Moore S., Cash J. D. A radioimmunoassay for platelet factor 4. Thromb Res. 1976 Jan;8(1):51–58. doi: 10.1016/0049-3848(76)90122-5. [DOI] [PubMed] [Google Scholar]
  8. Carlson T. H., Simon T. L., Atencio A. C. In vivo behavior of human radioiodinated antithrombin III: distribution among three physiologic pools. Blood. 1985 Jul;66(1):13–19. [PubMed] [Google Scholar]
  9. GREENWOOD F. C., HUNTER W. M., GLOVER J. S. THE PREPARATION OF I-131-LABELLED HUMAN GROWTH HORMONE OF HIGH SPECIFIC RADIOACTIVITY. Biochem J. 1963 Oct;89:114–123. doi: 10.1042/bj0890114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hamilton P. J., Allardyce M., Ogston D., Dawson A. A., Douglas A. S. The effect of age upon the coagulation system. J Clin Pathol. 1974 Dec;27(12):980–982. doi: 10.1136/jcp.27.12.980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Handin R. I., McDonough M., Lesch M. Elevation of platelet factor four in acute myocardial infarction: measurement by radioimmunoassay. J Lab Clin Med. 1978 Feb;91(2):340–349. [PubMed] [Google Scholar]
  12. Kaplan K. L., Nossel H. L., Drillings M., Lesznik G. Radioimmunoassay of platelet factor 4 and beta-thromboglobulin: development and application to studies of platelet release in relation to fibrinopeptide A generation. Br J Haematol. 1978 May;39(1):129–146. doi: 10.1111/j.1365-2141.1978.tb07135.x. [DOI] [PubMed] [Google Scholar]
  13. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  14. Lane D. A., Ireland H., Wolff S., Ranasinghe E., Dawes J. Detection of enhanced in vivo platelet alpha-granule release in different patient groups--comparison of beta-thromboglobulin, platelet factor 4 and thrombospondin assays. Thromb Haemost. 1984 Oct 31;52(2):183–187. [PubMed] [Google Scholar]
  15. Lau H. K., Rosenberg J. S., Beeler D. L., Rosenberg R. D. The isolation and characterization of a specific antibody population directed against the prothrombin activation fragments F2 and F1 + 2. J Biol Chem. 1979 Sep 25;254(18):8751–8761. [PubMed] [Google Scholar]
  16. Ludlam C. A., Moore S., Bolton A. E., Pepper D. S., Cash J. D. The release of a human platelet specific protein measured by a radioimmunoassay. Thromb Res. 1975 Jun;6(6):543–548. doi: 10.1016/0049-3848(75)90066-3. [DOI] [PubMed] [Google Scholar]
  17. Marcum J. A., Atha D. H., Fritze L. M., Nawroth P., Stern D., Rosenberg R. D. Cloned bovine aortic endothelial cells synthesize anticoagulantly active heparan sulfate proteoglycan. J Biol Chem. 1986 Jun 5;261(16):7507–7517. [PubMed] [Google Scholar]
  18. Marcum J. A., Conway E. M., Youssoufian H., Rosenberg R. D. Anticoagulantly active heparin-like molecules from cultured fibroblasts. Exp Cell Res. 1986 Sep;166(1):253–258. doi: 10.1016/0014-4827(86)90525-2. [DOI] [PubMed] [Google Scholar]
  19. Marcum J. A., Fritze L., Galli S. J., Karp G., Rosenberg R. D. Microvascular heparin-like species with anticoagulant activity. Am J Physiol. 1983 Nov;245(5 Pt 1):H725–H733. doi: 10.1152/ajpheart.1983.245.5.H725. [DOI] [PubMed] [Google Scholar]
  20. Marcum J. A., McKenney J. B., Rosenberg R. D. Acceleration of thrombin-antithrombin complex formation in rat hindquarters via heparinlike molecules bound to the endothelium. J Clin Invest. 1984 Aug;74(2):341–350. doi: 10.1172/JCI111429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Meade T. W., Chakrabarti R., Haines A. P., North W. R., Stirling Y. Characteristics affecting fibrinolytic activity and plasma fibrinogen concentrations. Br Med J. 1979 Jan 20;1(6157):153–156. doi: 10.1136/bmj.1.6157.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Meade T. W., North W. R., Chakrabarti R., Haines A. P., Stirling Y. Population-based distributions of haemostatic variables. Br Med Bull. 1977 Sep;33(3):283–288. doi: 10.1093/oxfordjournals.bmb.a071448. [DOI] [PubMed] [Google Scholar]
  23. Nossel H. L., Ti M., Kaplan K. L., Spanondis K., Soland T., Butler V. P., Jr The generation of fibrinopeptide A in clinical blood samples: evidence for thrombin activity. J Clin Invest. 1976 Nov;58(5):1136–1144. doi: 10.1172/JCI108566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nossel H. L., Younger L. R., Wilner G. D., Procupez T., Canfield R. E., Butler V. P., Jr Radioimmunoassay of human fibrinopeptide A. Proc Natl Acad Sci U S A. 1971 Oct;68(10):2350–2353. doi: 10.1073/pnas.68.10.2350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nossel H. L., Yudelman I., Canfield R. E., Butler V. P., Jr, Spanondis K., Wilner G. D., Qureshi G. D. Measurement of fibrinopeptide A in human blood. J Clin Invest. 1974 Jul;54(1):43–53. doi: 10.1172/JCI107749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nosslin B. Analysis of disappearance time-curves after single injection of labelled proteins. Ciba Found Symp. 1972;9:113–130. doi: 10.1002/9780470719923.ch7. [DOI] [PubMed] [Google Scholar]
  27. Odegärd O. R., Fagerhol M. K., Lie M. Heparin cofactor activity and antithrombin III concentration in plasma related to age and sex. Scand J Haematol. 1976 Oct;17(4):258–262. doi: 10.1111/j.1600-0609.1976.tb01183.x. [DOI] [PubMed] [Google Scholar]
  28. Reeve E. B., Leonard B., Wentland S. H., Damus P. Studies with 131I-labelled antithrombin III in dogs. Thromb Res. 1980 Nov 15;20(4):375–389. doi: 10.1016/0049-3848(80)90277-7. [DOI] [PubMed] [Google Scholar]
  29. Rodbard D., Lenox R. H., Wray H. L., Ramseth D. Statistical characterization of the random errors in the radioimmunoassay dose--response variable. Clin Chem. 1976 Mar;22(3):350–358. [PubMed] [Google Scholar]
  30. Rodbard D. Statistical quality control and routine data processing for radioimmunoassays and immunoradiometric assays. Clin Chem. 1974 Oct;20(10):1255–1270. [PubMed] [Google Scholar]
  31. Shapiro S. S., Martinez J. Human prothrombin metabolism in normal man and in hypocoagulable subjects. J Clin Invest. 1969 Jul;48(7):1292–1298. doi: 10.1172/JCI106095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Stern D., Nawroth P., Marcum J., Handley D., Kisiel W., Rosenberg R., Stern K. Interaction of antithrombin III with bovine aortic segments. Role of heparin in binding and enhanced anticoagulant activity. J Clin Invest. 1985 Jan;75(1):272–279. doi: 10.1172/JCI111685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Teitel J. M., Bauer K. A., Lau H. K., Rosenberg R. D. Studies of the prothrombin activation pathway utilizing radioimmunoassays for the F2/F1 + 2 fragment and thrombin--antithrombin complex. Blood. 1982 May;59(5):1086–1097. [PubMed] [Google Scholar]
  34. Thaler E., Lechner K. Antithrombin III deficiency and thromboembolism. Clin Haematol. 1981 Jun;10(2):369–390. [PubMed] [Google Scholar]
  35. Zahavi J., Jones N. A., Leyton J., Dubiel M., Kakkar V. V. Enhanced in vivo platelet "release reaction" in old healthy individuals. Thromb Res. 1980 Feb 1;17(3-4):329–336. doi: 10.1016/0049-3848(80)90067-5. [DOI] [PubMed] [Google Scholar]

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