Systemic Thrombin Generation and Activity Resistant to Low Molecular Weight Heparin Administered Prior to Streptokinase in Patients with Acute Myocardial Infarction

Summary

One hundred patients were included in a randomized open trial to assess the systemic factor Xa (FXa) and thrombin inhibitory effect as well as the safety profile of low molecular weight heparin (LMWH) given subcutaneously in conjunction with streptokinase (SK) in patients with acute myocardial infarction (MI). The treatment was initiated prior to SK, followed by repeated injections every 12 h for 7 days, using a dose of 150 anti-Xa units per kg body weight. The control group received unfractionated heparin (UFH) 12,500 IU subcutaneously every 12 h for 7 days, initiated 4 h after start of SK infusion. All patients received acetylsalicylic acid (ASA) initiated prior to SK.

Serial blood samples were collected prior to and during the first 24 h after initiation of SK infusion for determination of prothrombin fragment 1+2 (Fl+2), thrombin-antithrombin III (TAT) complexes, fibrinopeptide A (FPA) and cardiac enzymes. Bleeding complications and adverse events were carefully accounted for.

Infarct characteristics, as judged by creatine kinase MB isoenzyme (CK-MB) and cardiac troponin T (cTnT), were similar in both groups of patients.

A comparable transient increase in Fl+2, TAT and FPA was noted irrespective of heparin regimen. Increased anti-Xa activity in patients given LMWH prior to thrombolytic treatment had no impact on indices of systemic thrombin activation.

The incidence of major bleedings was significantly higher in patients receiving LMWH as compared to patients receiving UFH. However, the occurrence of bleedings was modified after reduction of the initial LMWH dose to 100 anti-Xa units per kg body weight.

In conclusion, systemic FXa- and thrombin activity following SK-infusion in patients with acute MI was uninfluenced by conjunctive LMWH treatment.

• References

• 1 Falk E. Plaque-rupture with severe preexisting stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal and occlusive thrombi. Br Heart J 1983; 50: 127-134
• 2 Davis MJ, Thomas AC. Plaque fissuring the cause of acute myocardial infarction, sudden ischemic death and crescendo angina. Br Heart J 1985; 53: 363-373
• 3 Chesebro JH, Badimon JJ, Ortiz AF, Meyer BJ, Fuster V. Conjunctive antithrombotic therapy for thrombolysis in myocardial infarction. AJC 1993; 72: 66G-74G
• 4 GISSI. Long term effects of intravenous thrombolysis in acute myocardial infarction. Lancet 1987; 02: 871-874
• 5 ISIS 2 Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither in 17,187 cases of suspected acute myocardial infarction: ISIS 2. Lancet 1988; 02: 349-360
• 6 GISSI-2: a factorial randomized trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction. Lancet 1990; 336: 65-71
• 7 ISIS-3 Collaborative Group. ISIS-3 a randomized comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs heparin alone among 41,299 cases of suspected acute myocardial infarction. Lancet 1992; 01: 753-770
• 8 The GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673-692
• 9 Hirsh J, Levine MN. Low molecular weight heparin. Review article. Blood 1992; 79: 1-17
• 10 Barrowcliffe TW, Johnson EA, Thomas DP. Low molecular weight heparin. Biochemistry of anticoagulant actions in vitro. John Wiley & Sons, Chichester; New York, Brisbane, Toronto, Singapore: 1992
• 11 Teitel JM, Rosenberg RD. Protection of factor Xa from neutralization by the heparin-antithrombin complex. J Clin Invest 1983; 71: 1383-1391
• 12 Ellis V, Scuffy MF, Kakkar VV. The acceleration of the inhibition of platelet prothrombinase complex by heparin. Biochem J 1986; 233: 161-165
• 13 Schoen P, Lindhout T, Willems G, Hemker HC. Antithrombin III-dependent antiprothrombinase activity of heparin and heparin fragments. J Biol Chem 1989; 264: 100002-100007
• 14 Suzuki K, Stenflo J, Dahlbaäck B, Teodorsson B. Inactivation of human coagulation factor V by activated protein C. J Biol Chem 1983; 258: 1914-1920
• 15 Odegaard BH, Mann KG. Proteolysis of factor Va by factor Xa and activated protein C. J Biol Chem 1987; 262: 11233-11238
• 16 Rasmanis G, Vesterqvist OGréen, Edhag o, Henriksson P. Evidence of increased platelet activation after thrombolysis in patients with acute myocardial infarction. Br Heart J 1992; 68: 374-376
• 17 Lee CD, Mann KG. Activation/inactivation of human factor V by plasmin. Blood 1989; 73 (01) 185-190
• 18 Varadi K, Philapitsch A, Santa T, Schwartz HP. The effect of plasmin on protein C and activated protein C. Circ 1992; 86: 1-736a
• 19 Gruber A, Pal A, Kiss RG, Sas G, Griffin JH. Generation of activated protein C during thrombolysis. Lancet 1993; 342: 1275-1276
• 20 Seegers WH, Nieff M, Schafer JA. Note on the adsorption of thrombin on fibrin. Science (Wash DC) 1945; 101: 520-521
• 21 Liu CY, Nossel HL, Kaplan KL. The binding of thrombin to fibrin. J Biol Chem 1979; 254: 10421-10425
• 22 Eisenberg PR, Siegel JE, Abendschein DR, Miletich JP. Importance of factor Xa in determining the procoagulant activity of whole-blood clots. J Clin Invest 1993; 91: 1877-1883
• 23 Francis CW, Markham RE, Barlow GH, Florach TM, Dobrzynski DM, Marder VJ. Thrombin activity of fibrin thrombi and soluble plasma derivates. J Lab Clin Med 1983; 102: 220-230
• 24 Nilsen DWT, Brosstad F, Kierulf P, Godal HC. Binding of various thrombin fractions to fibrin and the influence of AT-III on their adsorption. Thromb Haemost 1986; 86: 352-356
• 25 Farstad IN, Nilsen DWT, Ruyter R, Godal HC. Thrombin activity in human pulmonary emboli obtained at autopsy. Thromb Res 1990; 59: 879-882
• 26 Hogg PJ, Jackson CM. Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: Implications for heparin efficacy. Proc Natl Acad Sci (USA) 1989; 86: 3619-3623
• 27 Weitz JL, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III independent inhibitors. J Clin Invest 1990; 86: 385-391
• 28 Bloom AL. The release of thrombin from fibrin by fibrinolysis. Br J Haematol 1962; 08: 129-133
• 29 Seitz R, Blanke H, Pratorius G, Strauer BE, Egbring R. Increased thrombin activity during thrombolysis. Thromb Haemost 1988; 59 (03) 541-542
• 30 Brandt DG, Gates RC, Kathy CE. et al Quantifying the CK-MB isoenzyme of creatine kinase with the Abbott IMX Immunoassay Analyzer. Clin Chem 1990; 36: 375-378
• 31 Hetland Ø, Gøransson L, Nilsen DWT. Cardiac troponin T immunoassay on biotin-streptavidin-coated microplates: preliminary performance in acute myocardial infarction. Scand J Lab Invest 1995; 55: 701-713
• 32 Nossel HI, Yudelman I, Canfield R, Butler VP, Spanondis K, Wilner GD, Quereshi GD. Measurement of fibrinopeptide A in human blood. J Clin Invest 1974; 54: 43-53
• 33 Pelzer H, Schwartz A, Heimburger N. Determination of human thrombin-antithrombin III complex in plasma with an enzyme-linked immunosorbent assay. Thromb Haemost 1988; 59: 101-106
• 34 Pelzer H, Sch warz, Stuber W. Determination of human prothrombin activation fragment 1+2 in plasma with an antibody against a synthetic peptide. Thromb Haemost 1991; 65: 153-159
• 35 ten Cate H, Lamping RJ, Henny P, Prins A, ten Cate JW. Automated amidolytic method for determining heparin, a heparinoid, and a low-MW heparin fragment, based on their anti-Xa activity. Clin Chem 1984; 30: 860-864
• 36 Eisenberg PR, Miletech JP, Sobel BE, Jaffe AS. Differential effects of activation of prothrombin by streptokinase compared with urokinase and tissue-type plasminogen activator (t-PA). Thromb Res 1988; 50: 707-717
• 37 Ewald GA, Eisenberg PR. Plasmin-mediated activation of contact system in response to pharmacological thrombolysis. Circulation 1995; 91: 28-36
• 38 Galvani M, Abendschein DR, Ferrini D, Ottani F, Rusticali F, Eisenberg PR. Failure of fixed dose intravenous heparin to suppress increases in thrombin activity after coronary thrombolysis with streptokinase. J Am Coll Cardiol 1994; 24: 1445-1452
• 39 Merlini PA, Cattaneo M, Spinola A, Ardissino D, Oltrona L, Belli C, Mannucci PM. Activation of the hemostatic system during thrombolytic therapy. Am J Cardiol 1993; 72: 59G-65G
• 40 Weitz JI. Elevated fibrinopeptide A and B during thrombolytic therapy: Real or artefactual?. Thromb Haemost 1996; 75: 529-535
• 41 Seitz R, Pelzer H, Immel A, Egbring R. Prothrombin activation by thrombolytic agents. Fibrinolysis 1993; 07: 109-115
• 42 Sitko GR, Ramjit DR, Stabilito II, Lehman D, Lynch JJ, Vlasuk GP. Conjunctive enhancement of enzymatic thrombolysis and prevention of thrombotic reocclusion with the selective factor Xa inhibitor, tick anticoagulant peptide. Comparison to hirudin and heparin in a canine model of acute coronary artery thrombosis. Circulation 1992; 05 (02) 805-815
• 43 Nesvold A, Kontny F, Abildgaard U, Dale J. Safety of high doses of low molecular weight heparin (Fragmin) in acute myocardial infarction. A dose-finding study. Thromb Res 1991; 64: 579-587