Influence of Long Term Oral Anticoagulants upon Prothrombin Fragment 1 + 2, Thrombin-Antithrombin III Complex and D-Dimer Levels in Patients Affected by Proximal Deep Vein Thrombosis

Summary

We have investigated the influence of long term oral anticoagulants (OAC) upon the plasma levels of prothrombin fragment 1 + 2 (F1 + 2), of thrombin-antithrombin III complexes (TAT) and of D-Dimer in 20 patients affected by a proximal deep vein thrombosis (DVT) diagnosed by ultrasonic duplex scanning. Patients (63 ± 17 years, mean ± SD) were sampled at the beginning of the OAC treatment (day 1), which was started 1 to 6 days after diagnosis confirmation and full heparinization, and then 8, 35 and 92 days after. The results were compared to those obtained in a blood donor population (39 ± 10 years) and to an age-matched healthy population (63 ± 19 years). The mean INR determined on days 8, 35 and 92 were almost identical (2.8 ± 0.7, 2.9 ± 0.9 and 2.8 ± 0.6 respectively). In contrast, highly significant variations of the three markers were recorded during the observation period. Eight days after the beginning of OAC, increased levels of TAT complexes were associated with subnormal levels of F1 + 2 suggesting persistence of a hypercoagulable state. On the further sampling times, TAT complexes were in the normal range while F1 + 2 were far below the normal range. Between day 1 and day 92, the levels of D-Dimer continuously decreased reflecting a long-term fibrinolytic process.

This study clearly indicates that high INR are not systematically associated with very low F1 + 2 levels, particularly in the acute phase of thrombosis. Whether or not it is possible to reduce the intensity of the anticoagulant treatment 1 month after its initiation on the basis of very low levels of F1 + 2 can only be determined by prospective clinical trials.

• References

• 1 Pelzer H, Schwarz A, Stuber W. Determination of human prothrombin activation fragment 1 + 2 in plasma with an antibody against a synthetic peptide. Thromb Haemostas 1991; 65: 153-159
• 2 Pelzer H, Schwarz A, Heimburger N. Determination of human thrombin-antithrombin III complex in plasma with an enzyme-linked immunosorbent assay. Thromb Haemostas 1988; 59: 101-106
• 3 Gaffney PJ, Brasher M. Subunit structure of the plasmin induced degradation products of cross linked fibrin. Biochem Biophys Acta 1973; 295: 308-313
• 4 Whitaker AN, Elms MJ, Masci PP, Bundesen PG, Rylatt DB, Webber AJ, Bunce IH. Measurement of cross linked fibrin derivatives in plasma: an immunoassay using monoclonal antibodies. Clin Pathol 1984; 37: 882-887
• 5 Estival M, Pelzer H, Sié P, Pichon J, Boccalon H, Boneu B. Prothrombin fragment 1 + 2, thrombin-antithrombin III complexes and D-dimers in acute deep vein thrombosis: effects of heparin treatment. Br J Haematol 1991; 78: 421-424
• 6 Rowbotham B, Caroll P, Whitaker A, Bunce I, Cobcroft R, Elms MJ, Masci P, Bundesen P, Rylatt D, Webber A. Measurement of crosslinked fibrin derivatives. Use in the diagnosis of venous thrombosis. Thromb Haemostas 1987; 57: 59-61
• 7 Heaton D, Billings J, Hickton C. Assessement of D-Dimer assays for the diagnosis of deep vein thrombosis. J Lab Clin Med 1987; 110: 588-591
• 8 Ott P, Astrup L, Hartuing JensenR, Nyeland B, Pederson B. Assessment of D-Dimer in plasma: diagnosis value in suspected deep venous thrombosis of the leg. Acta Med Scand 1988; 224: 263-267
• 9 Bounameaux H, Schneider P, De Moerloose P, Krähenbühl B. Measurement of plasma D-Dimer for diagnosis of deep venous thrombosis. Am J Clin Pathol 1989; 91: 82-85
• 10 Elias A, Aillaud M, Roul C, Monteil O, Vilain Ph, Serradimigni A, Juhan-Vague I. Assessment of D-Dimer measurement by ELISA or latex methods in deep vein thrombosis diagnosed by ultrasonic duplex scanning. Fibrinolysis 1990; 4: 237-240
• 11 Van Bergen P, Knot E, Jonker J, De Boer A, De Maat M. Is quantitative determination of fibrin(ogen) degradation products and thrombin-antithrombin III complexes useful to diagnose deep venous thrombosis in out-patients?. Thromb Haemostas 1989; 62: 1043-1045
• 12 Boneu B, Bes G, Pelzer H, Sié P, Boccalon H. D-Dimers. thrombin-antithrombin III complexes and prothrombin fragments F1 + 2: diagnosis value in clinically suspected deep vein thrombosis. Thromb Haemostas 1991; 65: 28-32
• 13 Conway EM, Bauer KA, Barzegar S, Rosenberg RD. Suppression of hemostatic system activation by oral anticoagulants in the blood of patients with thrombotic diatheses. J Clin Invest 1989; 80: 1535-1544
• 14 Mannucci PM, Bottasso B, Tripodi A. Prothrombin fragment 1 + 2 and intensity of treatment with oral anticoagulants. Thromb Haemostas 1991; 66: 741
• 15 Millenson MM, Bauer KA, Kistler JP, Barzegar S, Tulin L, Rozenberg RD. Monitoring “Mini-Intensity”� anticoagulation with Warfarin: comparison of the prothrombin time using a sensitive thromboplastin with prothrombin fragment F1 + 2 levels. Blood 1992; 79: 2034-2038
• 16 Elias A, Legorff G, Bouvier JL, Benichou M, Serradimigni A. Value of real time B mode ultrasound imaging in the diagnosis of deep vein thrombosis of the lower limit. Int Angiol 1987; 6: 175-182
• 17 Lensing A, Prandoni P, Brandjes D, Huisman PM, Vigo M, Tomasella G, Krekt J, Late JW, Huisman MW, Büller HR. Detection of deep vein thrombosis by real time B mode ultrasonography. N Engl J Med 1989; 320: 342-345
• 18 Bauer KA, Weiss LM, Sparow D, Vokonas PS, Rozenberg RD. Aging-associated changes in indices of thrombin generation and protein C activation in humans. Normative aging study. J Clin Invest 1987; 80: 1527-1534
• 19 Cadroy Y, Perrejean D, Fontan B, Sié P, Boneu B. Influence of aging on the activity of the hemostatic system: prothrombin fragment 1 + 2. thrombin-antithrombin III complexes and D-Dimers in 80 healthy subjects with age ranging from 20 to 94 years. Nouv Rev Fr Hematol 1992; 34: 43-46
• 20 Kario K, Matsuo T, Kobayashi H. Which factors affect high D-Dimer levels in the elderly. Thromb Res 1991; 62: 501-508