Download PDF
Thromb Haemost 1988; 59(02): 133-137
DOI: 10.1055/s-0038-1642741
Original Articles
Schattauer GmbH Stuttgart

Monitoring of Hemostasis Parameters During Coronary Thrombolysis with Recombinant Tissue-Type Plasminogen Activator

D C Stump
1   The Departments of Medicine and Biochemistry, University of Vermont College of Medicine, Burlington, VT, the Department of Internal Medicine, University of Michigan, Ann Arbor, Ml, and Genentech, Inc., South San Francisco, CA, USA
,
E J Topol
1   The Departments of Medicine and Biochemistry, University of Vermont College of Medicine, Burlington, VT, the Department of Internal Medicine, University of Michigan, Ann Arbor, Ml, and Genentech, Inc., South San Francisco, CA, USA
,
A B Chen
1   The Departments of Medicine and Biochemistry, University of Vermont College of Medicine, Burlington, VT, the Department of Internal Medicine, University of Michigan, Ann Arbor, Ml, and Genentech, Inc., South San Francisco, CA, USA
,
A Hopkins
1   The Departments of Medicine and Biochemistry, University of Vermont College of Medicine, Burlington, VT, the Department of Internal Medicine, University of Michigan, Ann Arbor, Ml, and Genentech, Inc., South San Francisco, CA, USA
,
D Collen
1   The Departments of Medicine and Biochemistry, University of Vermont College of Medicine, Burlington, VT, the Department of Internal Medicine, University of Michigan, Ann Arbor, Ml, and Genentech, Inc., South San Francisco, CA, USA
› Author Affiliations
Further Information

Publication History

Received 06 October 1987

Accepted 29 October 1987

Publication Date:
21 May 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

The monitoring of changes in the blood coagulation and fibrinolytic systems during thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA) may be complicated by artifacts due to in vitro activation after blood collection and to interference of other agents (e. g., heparin) in the assays. In 106 patients with early acute myocardial infarction, infused with 150 mg of rt-PA (G11044) intravenously over 5 to 8 hours, blood samples were collected into liquid citrate supplemented with the plasmin inhibitor aprotinin (200 KlU/ml plasma) or on a lyophilized mixture of acidified citrate and the synthetic t-PA inhibitor D-Phe-Pro-Arg-CH2Cl (PPACK). A good correlation between precipitable (sulphite) and functional (clotting rate) fibrinogen levels was observed in plasma collected on citrate before therapy (r = 0.76) and in samples collected after 3 hours on either aprotinin (r = 0.87) or PPACK (r = 0.82). Precipitable fibrinogen levels were approximately 10% higher than functional level, in baseline samples collected on citrate alone and approximately 20% higher in 3 hour samples collected on either PPACK or aprotinin. Fibrinogen levels measured with both assays correlated well, but were somewhat higher in samples collected on PPACK than on aprotinin. rt-PA antigen levels assayed in plasma collected in either inhibitor correlated well (r = 0.90) but were 10-20% higher in PPACK containing samples. Addition of heparin up to 9 units/ml to plasma had no effect on the functional fibrinogen assay.

Even with these precautions for assay artifact, a very poor correlation (r =-0.15) was observed between the plasma rt-PA level and the residual functional fibrinogen level, both after 3 hours and towards the end of the rt-PA infusion. A decrease of the fibrinogen level at the end of the infusion to below 1 g/l was observed in 36% of the patients and to below 0.5 g/l in 11%. Optimal monitoring of hemostasis during rt-PA infusion is achieved by fibrinogen assays with a clotting rate method on samples collected on either PPACK or aprotinin. Heparin at therapeutic levels does not interfere with this assay.

Keywords

Thrombolytic therapy - Fibrinogen assays - In vitro fibri - nogenolysis - Fibrinolysis - Laboratory monitoring
 

  • References

  • 1 Collen D, Topol EJ, Tiefenbrunn AJ, Gold HK, Weisfeldt ML, Sobel BE, Leinbach RC, Brinker JA, Ludbrook PA, Yasuda T, Bulkley BH, Robison AK, Hutter AM, Bell WR, Spadaro JJ, Khaw BA, Grossbard EB. Coronary thrombolysis with recombinant human tissue-type plasminogen activator: a prospective randomized, placebo controlled trial. Circulation 1984; 70: 1012-1017
    CrossrefPubMedGoogle Scholar
  • 2 TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) trial. N Engl J Med 1985; 312: 932-936
    PubMedGoogle Scholar
  • 3 Verstraete M, Bernard R, Bory M, Brower RW, Collen D, de Bono DP, Erbel R, Huhmann W, Lennane RJ, Lubsen J, Mathey D, Meyer J, Michels HR, Rutsch W, Schartl M, Schmidt W, Uebis R, von Essen R. Randomised trial of intravenous recombinant human tissue-type plasminogen activator versus intravenous streptokinase in acute myocardial infarction. Lancet 1985; 1: 842-847
    PubMedGoogle Scholar
  • 4 Verstraete M, Bleifeld W, Brower RW, Charbonnier B, Collen D, de Bono DP, Dunning AJ, Lennane RJ, Lubsen J, Mathey DG, Michel PL, Raynaud PH, Schofer J, Vahanian A, Vanhaecke J, van de Kley GA, Van de Werf F, von Essen R. Double-blind randomised trial of intravenous tissue-type plasminogen activator versus placebo in acute myocardial infarction. Lancet 1985; 2: 965-969
    PubMedGoogle Scholar
  • 5 Collen D, Bounameaux H, De Cock F, Lijnen HR, Verstraete M. Analysis of coagulation and fibrinolysis during intravenous infusion of recombinant human tissue-type plasminogen activator (rt-PA) in patients with acute myocardial infarction. Circulation 1986; 73: 511-517
    CrossrefPubMedGoogle Scholar
  • 6 Gold HK, Fallon JT, Yasuda T, Leinbach RC, Khaw BA, Newell JB, Guerrero JL, Vislosky FM, Hoyng CF, Grossbard EB, Collen D. Coronary thrombolysis with recombinant human tissue-type plasminogen activator. Circulation 1984; 70: 700-707
    CrossrefPubMedGoogle Scholar
  • 7 Topol EJ, Bell WR, Weisfeldt ML. Coronary thrombolysis with recombinant tissue-type plasminogen activator. A hematologic and pharmacologic study Ann Intern Med 1985; 103: 837-843
    CrossrefPubMedGoogle Scholar
  • 8 Holvoet P, Lijnen HR, Collen D. A monoclonal antibody preventing binding of tissue-type plasminogen activator (t-PA) to fibrin, useful to monitor fibrinogen breakdown during t-PA infusion. Blood 1986; 67: 1482-1487
    PubMedGoogle Scholar
  • 9 Mohler MA, Refino CJ, Chen SA, Chen AB, Hotchkiss AJ. D-Phe-Pro-Arg-chloromethylketone: its potential use in inhibiting the formation of in vitro artifacts in blood collected during tissue-type plasminogen activator thrombolytic therapy. Thromb Haemostas 1986; 56: 160-164
    PubMedGoogle Scholar
  • 10 Tiefenbrunn AJ, Graor RA, Robison AK, Lucas FV, Hotchkiss A, Sobel BE. Pharmacodynamics of tissue-type plasminogen activator characterized by computer-assisted simulation. Circulation 1986; 73: 1291-1299
    CrossrefPubMedGoogle Scholar
  • 11 Topol EJ, Califf RM, George BS, Kereiakis DJ, Abbottsmith CW, Candela RJ, Lee KL, Pitt B, Stack RS, O’Neill WW. A multi-center randomized trial of intravenous recombinant tissue plasminogen activator and immediate versus deferred angioplasty in acute myocardial infarction. N Engl J Med 1987; 317: 581-588
    CrossrefPubMedGoogle Scholar
  • 12 Holvoet P, Lijnen HR, Collen D. Characterization of functional domains in human tissue-type plasminogen activator with the use of monoclonal antibodies. Eur J Biochem 1986; 158: 173-177
    CrossrefPubMedGoogle Scholar
  • 13 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 37: 237-246
    PubMedGoogle Scholar
  • 14 Vermylen C, DeVreker RA, Verstraete M. A rapid enzymatic method for assay of fibrinogen fibrin polymerization time (FPT-test). Clin Chem Acta 1963; 8: 418-424
    CrossrefPubMedGoogle Scholar
  • 15 Rampling MW, Gaffney PJ. The sulphite precipitation method for fibrinogen measurement: its use on small sample in the presence of fibrinogen degradation products. Clin Chem Acta 1976; 67: 43-52
    CrossrefPubMedGoogle Scholar
  • 16 Merskey C, Lalezari P, Johnson AJ. A rapid, simple, sensitive method for measuring fibrinolytic split products in human serum. Proc Soc Exp Biol Med 1969; 131: 871-875
    CrossrefPubMedGoogle Scholar
  • 17 Holvoet P, Cleemput H, Collen D. Assay of human tissue-type plasminogen activator (t-PA) with an enzyme-linked immunosorbent assay (ELISA) based on three murine monoclonal antibodies to t-PA. Thromb Haemostas 1985; 54: 684-687
    PubMedGoogle Scholar
  • 18 Gaffney PJ, Curtis AD. A collaborative study of a proposed international standard for tissue plasminogen activator (t-PA). Thromb Haemostas 1985; 53: 134-136
    PubMedGoogle Scholar