Markers of Hemostatic System Activation in Acute Deep Venous Thrombosis-Evolution during the First Days of Heparin Treatment

Summary

Fibrin D-Dimer (D-Di), prothrombin activation fragment (F 1+2) and thrombin-antithrombin III complexes (TAT) were measured using ELISA procedures in the plasma of patients with an acute deep venous thrombosis (DVT), at presentation and on days 2, 6 and 10 after initiation of heparin treatment. Patients were randomly allocated into two treatment groups: 44 patients received adapted doses of continuous intravenous unfractionated heparin (UH) whereas 47 received 1 mg/kg every twelve hours of a low molecular weight heparin (enoxaparin) subcutaneously. A phlebography and a perfusion lung scan were performed before inclusion and on day 10. Failure of therapy (n = 9) was defined by venogram worsening or confirmed pulmonary embolism. Improvement (n = 44) or stationary state (n = 38) were defined by venogram evolution in the absence of new leg scan defects.

At presentation, D-Di, F 1 + 2 and TAT were above cut-off values in 97, 66 and 89% of patients respectively. D-Di levels correlated with the extent of venous thrombosis whereas TAT and F 1 + 2 did not. Mean levels of D-Di decreased sharply during the first days of treatment but were still abnormal on day 10. A secondary increase of D-Di on days 6 or 10 by more than 3 μg/ml occurred in 4 of the 9 patients who developed a thromboembolic recurrence but in none of the 72 patients who had a more favorable outcome. F 1 + 2 and TAT time-courses were not related to clinical evolution. In the Enoxaparin group, there was no relationship between antifactor Xa activities and any biological markers. TAT and F 1 + 2 levels fell on day 2 and remained stable until day 10. In contrast, in the UH group, TAT and F 1 + 2 did not significantly decrease on day 2, probably due to a delay in dose adaptation, but they declined slowly until day 10.

In conclusion, D-Di displays a higher sensitivity than F 1 + 2 or TAT for the diagnosis of D\T. D-Di, but not TAT or F 1 + 2, follow-up seems to be of potential value for early detection of recurrency. Hemostatic activation is controlled earlier by fixed doses of a low molecular weight heparin, irrespective of the plasma anti-factor Xa activities, than by unfractionated heparin at adapted doses.

^*P. Alexandre (CHU, Nancy); J. Amiral (Diagnostica-Stago, Asnières); J. Bienvenu (CHU, Lyon); J. Y. Borg (CHU, Rouen); E Bridey (CHU, Clamart); L. Cahan (Behring, Rueil Malmaison); S. Combe (Rhône Poulenc-Rorer, Neuilly); B. Delahousse (CHU, Tours); M. Dreyfus (CHU, Clamart); C. Gauthier (CHG, Dole); I. Juhan-Vague (CHU, Marseille La Conception); D. Landauer (Rhòne Poulenc-Rorer, Neuilly); J. J. Musitelli (Behrirg, Rueil Malmaison); P. Pouzol (CHU, Grenoble); F. Raisky (CHG, Dole); J. Reynaud (CHU, St-Etienne); P. Sié (CHU, Toulouse-Purpan); O. Sitbon (CHU, Bicêtre); M. C. Treziac (CHU, Lyon).

• References

• 1 Rylatt DB, Blake AS, Cottis LE, Massingham DA, Fletcher WA, Masci PP, Whitaker AN, Elms M, Bunce I, Webber AJ, Wyatt D, Bundesen PG. An immunoassay for human D-Dimer using monoclonal antibodies. Thromb Res 1983; 31: 767-778
• 2 Pelzer H, Schwarz A, Stiiber W. Determination of human prothrombin activation fragment 1 + 2 in plasma with an antibody against a synthetic peptide. Thromb Haemostas 1991; 65: 153-159
• 3 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
• 4 Rowbotham BJ, Carroll P, Whitaker AN, Bunce IH, Cobcroft RG, Elms MJ, Masci PP, Bundesen PG, Rylatt DB, Webber AJ. Measurement of crosslinked fibrin derivatives – use in the diagnosis of venous thrombosis. Thromb Haemostas 1987; 57: 59-61
• 5 Heaton DC, Billings JD, Hickton CM. Assessment of D-dimer assays for the diagnosis of deep vein thrombosis. J Lab Clin Med 1987; 110: 588-591
• 6 Declerck PJ, Mombaerts P, Holvoet P, De MolM, Collen D. Fibrinolytic response and fibrin fragment D-Dimer levels in patients with deep vein thrombosis. Thromb Haemostas 1987; 58: 1024-1029
• 7 Ott P, Astrup L, Jensen RH, Nyeland B, Pedersen B. Assessment of D-Dimer in plasma: diagnostic value in suspected deep venous thrombosis of the leg. Acta Med Scand 1988; 224: 263-267
• 8 Mirshahi M, Soria C, Soria J, Mirshahi M, Faivre R, Kieffer Y, Bassand JP, Toulemonde F, Caen J. Changes in plasma fibrin degradation products as a marker of thrombus evolution in patients with deep vein thrombosis. Thromb Res 1988; 51: 295-302
• 9 van BergenPFMM, Knot EAR, Jonker JJC, De BoerAC, De MaatMPM. Is quantitative determination of fibrin(ogen) degradation products and thrombin-antithrombin III complexes useful to diagnose deep venous thrombosis in outpatients. Thromb Haemostas 1989; 62: 1043-1045
• 10 Bounameaux H, Schneider PA, Reber G, De MoerloosePh, Krahenbuhl B. Measurement of plasma D-Dimer for diagnosis of deep venous thrombosis. Am J Clin Pathol 1989; 91: 82-85
• 11 Boisclair MD, Lane DA, Wilde JT, Ireland H, Preston FE, Ofosu FA. A comparative evaluation of assays for markers of activated coagulation and/or fibrinolysis: thrombin-antithrombin complex, D-dimer and fibrinogen/fibrin fragment E antigen. Brit J Haematol 1990; 74: 471-479
• 12 Elias A, Aillaud MF, Roul C, Montail O, Villain 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
• 13 Speiser W, Mallek R, Koppensteiner R, Stiimpflen A, Kapiotis S, Minar E, Ehringer H, Lechner K. D-Dimer and TAT measurement in patients with deep vein thrombosis: utility in diagnostic and judgement of anticoagulant treatment effectiveness. Thromb Haemostas 1990; 64: 196-201
• 14 Boneu B, Bes G, Pelzer H, Siè P, Boccalon H. D-Dimers, thrombin antithrombin III complexes and prothrombin fragments 1+2; diagnostic value in clinically suspected deep vein thrombosis. Thromb Haemostas 1991; 65: 28-32
• 15 Blanke H, Praetorius G, Leschke M, Seitz R, Egbring R, Strauer BE. Die Bedeutung des Thrombin-Antithrombin III-Komplexes in der Diagnostik der Lungenembolie und der tiefen Venenthrombose – Vergleich mit Fibrinopeptid A, Plattchenfaktor 4 und Beta-Throm-boglobulin. Klin Wochenschr 1987; 65: 757-763
• 16 Hoek JA, Sturk A, Ten Cate JW, Lamping RJ, Berends F, Borm JJJ. Laboratory and clinical evaluation of an assay of thrombin-antithrombin III complexes in plasma. Clin Chem 1988; 34: 2058-2062
• 17 Estivals M, Pelzer M, Siè 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. Brit J Haematol 1991; 78: 421-424
• 18 Amelsberg A, Zurborn KH, Gartner U, Kiehne KH, Preube AK, Bruhn HD. Influence of heparin treatment on biochemical markers of an activation of the coagulation system. Thromb Res 1992; 66: 121-131
• 19 Simonneau G, Charbonnier B, Decousus H, Planchon B, Ninet J, Sie P, Silsiguen M, Combe S. Subcutaneous low molecular weight heparin compared with continuous intravenous unfractionated heparin in the initial treatment of proximal vein thrombosis. A multicenter randomized trial: DVTENOX study Arch Int Medicine. 1993. (in press)
• 20 Bridey F, Phlippoteau C, Simmoneau G, Musset D, Dreyfus M. Is D-Dimer measurement a marker of recurrence of thromboembolic disease. Thromb Haemostas 1991; 65: 981 (abstract)
• 21 Agnelli G, Borm J, Cosmi B, Levi M, Ten CateJW. Effects of standard heparin and low molecular weight heparin (KABI 2165) on fibrinolysis. Thromb Haemostas 1988; 60: 311-313
• 22 Hull RD, Raskob GE, Hirsh J, Jasy RM, Leclerc JR, Geerts WH, Rosenbloom D, Sackett DL, Anderson C, Harrison L, Gent M. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986; 315: 1109-1114
• 23 Samama MM, Combe S, Horellou MH, Augras D, True JB, Conard J, Girard P, Bara L, Poitout Ph. Anti Xa activity and prothrombinase inhibition in patients treated with two different doses of enoxaparin in gynaecologic surgery. Thromb Res 1991; 14: 29-37
• 24 Ofosu FA, Leclerc J, Blajchman MA. The low molecular weight heparin enoxaparin moderates factor VII and prothrombin consumption associated with elective knee surgery. Thromb Haemostas 1991; 65: 1298 (abstract)
• 25 Beguin S, Wielder SS, Lormeau JC, Hemker HC. The mode of action of CY 216 and CY222 in plasma. Thromb Haemostas 1992; 67: 33-41
• 26 Janvier G, Freyburger G, Winnock S, Dugrais G, Boisseau M, Boisserias P. An open trial of enoxaparin in the treatment of deep vein thrombosis of the leg. Haemostasis 1991; 21: 161-168