Pharmacodynamics of thrombolysis with recombinant tissue-type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction

D. C. Stump, R. M. Califf, E. J. Topol, K. Sigmon, D. Thornton, R. Masek, L. Anderson, D. Collen, W. W. O'Neill, J. A. Walton, E. R. Bates, S. G. Ellis, A. Schork, E. Kline, L. Gorman, R. Worden, B. Pitt, R. S. Stack, H. R. Phillips

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

Coagulation asnalysis was performed on blood samples from 386 patients with acute myocardial infarction drawn before, during, and after a continuous intravenous infusion of 150 mg recombinant tissue-type plasminogen activator (rt-PA) (Activase®). Plasma rt-PA rose to peak levels of 2.1 ± 3.1 μg/ml (mean ± SD). Fibrinogen levels measured by coagulation rate and by sulfite precipitation decreased from baseline levels of 3.0 ± 0.9 and 3.2 ± 1.0 g/l, respectively, to nadir levels of 1,4 ± 0.75 and 1.8 ± 0.92 g/l, respectively, and were associated with peak levels in serum of fibrinogen-degradation products (FDP) of 230 ± 470 μg/ml. Forty percent of patients exprienced a nadir functional-fibrinogen level of less than 1.0 g/l, whereas 20% fell below 0.5 g/l. Nadir fibrinogen levels did not correlate with patency of the infarct-related coronary artery at 90 minutes or with risk of coronary vessel reocclusion within 7-10 days. However, the risk of coronary artery reocclusion was inversely related to the baseline functional fibrinogen level (p = 0.0008), with the magnitude of its drop to nadir level (p = 0.0003) as well as to peak levels of FDP (p = 0.038). Quantitative blood loss correlated with all markers for systemic fibrinogenolysis including nadir fibrinogen level (r = -0.20, p = 0.0011), percent decrease of fibrinogen (r = 0.22, p = 0.001), and peak FDP levels (r = 0.14, p = 0.020). Both patients who experienced intracranial hemorrhage presented with high baseline fibrinogen levels and experienced extensive degradation of coagulable fibrinogen. Overall, patients at greatest risk of systemic fibrinogenolysis tended to be relatively older women with lower body weight. Peak plasma levels of t-PA antigen were weakly correlated with nadir-fibrinogen levels (r = 0.11, p = 0.041) and peak FDP levels (r = 0.12, p = 0.020), and also tended to be higher in older women of lowere body weight. Plasma levels of t-PA antigen were higher in nonoperated patients experiencing 'major' bleeding (3.4 versus 2.2 μg/ml, p = 0.002). These results indicate that changes in coagulation parameters are highly variable in the setting of thrombolytic treatment with t-PA of acute myocardial infarction, precluding their use for predictive monitoring of therapy in individual patients. Nonetheless, the overall pattern of pharmacodynamic behavior or rt-PA within a given population and its correlation with selected major clinical outcomes, particularly with risk of reocclusion and bleeding, will be most useful for the design of alternative administration schemes.

Original languageEnglish
Pages (from-to)1222-1230
Number of pages9
JournalCirculation
Volume80
Issue number5
StatePublished - Jan 1 1989
Externally publishedYes

Fingerprint

Tissue Plasminogen Activator
Fibrinogen
Myocardial Infarction
Coronary Vessels
Body Weight
Hemorrhage
Antigens
Sulfites
Intracranial Hemorrhages
Intravenous Infusions

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Pharmacodynamics of thrombolysis with recombinant tissue-type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction. / Stump, D. C.; Califf, R. M.; Topol, E. J.; Sigmon, K.; Thornton, D.; Masek, R.; Anderson, L.; Collen, D.; O'Neill, W. W.; Walton, J. A.; Bates, E. R.; Ellis, S. G.; Schork, A.; Kline, E.; Gorman, L.; Worden, R.; Pitt, B.; Stack, R. S.; Phillips, H. R.

In: Circulation, Vol. 80, No. 5, 01.01.1989, p. 1222-1230.

Research output: Contribution to journalArticle

Stump, DC, Califf, RM, Topol, EJ, Sigmon, K, Thornton, D, Masek, R, Anderson, L, Collen, D, O'Neill, WW, Walton, JA, Bates, ER, Ellis, SG, Schork, A, Kline, E, Gorman, L, Worden, R, Pitt, B, Stack, RS & Phillips, HR 1989, 'Pharmacodynamics of thrombolysis with recombinant tissue-type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction', Circulation, vol. 80, no. 5, pp. 1222-1230.
Stump, D. C. ; Califf, R. M. ; Topol, E. J. ; Sigmon, K. ; Thornton, D. ; Masek, R. ; Anderson, L. ; Collen, D. ; O'Neill, W. W. ; Walton, J. A. ; Bates, E. R. ; Ellis, S. G. ; Schork, A. ; Kline, E. ; Gorman, L. ; Worden, R. ; Pitt, B. ; Stack, R. S. ; Phillips, H. R. / Pharmacodynamics of thrombolysis with recombinant tissue-type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction. In: Circulation. 1989 ; Vol. 80, No. 5. pp. 1222-1230.
@article{4d364661f23a44629cb51ca141e4e19a,
title = "Pharmacodynamics of thrombolysis with recombinant tissue-type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction",
abstract = "Coagulation asnalysis was performed on blood samples from 386 patients with acute myocardial infarction drawn before, during, and after a continuous intravenous infusion of 150 mg recombinant tissue-type plasminogen activator (rt-PA) (Activase{\circledR}). Plasma rt-PA rose to peak levels of 2.1 ± 3.1 μg/ml (mean ± SD). Fibrinogen levels measured by coagulation rate and by sulfite precipitation decreased from baseline levels of 3.0 ± 0.9 and 3.2 ± 1.0 g/l, respectively, to nadir levels of 1,4 ± 0.75 and 1.8 ± 0.92 g/l, respectively, and were associated with peak levels in serum of fibrinogen-degradation products (FDP) of 230 ± 470 μg/ml. Forty percent of patients exprienced a nadir functional-fibrinogen level of less than 1.0 g/l, whereas 20{\%} fell below 0.5 g/l. Nadir fibrinogen levels did not correlate with patency of the infarct-related coronary artery at 90 minutes or with risk of coronary vessel reocclusion within 7-10 days. However, the risk of coronary artery reocclusion was inversely related to the baseline functional fibrinogen level (p = 0.0008), with the magnitude of its drop to nadir level (p = 0.0003) as well as to peak levels of FDP (p = 0.038). Quantitative blood loss correlated with all markers for systemic fibrinogenolysis including nadir fibrinogen level (r = -0.20, p = 0.0011), percent decrease of fibrinogen (r = 0.22, p = 0.001), and peak FDP levels (r = 0.14, p = 0.020). Both patients who experienced intracranial hemorrhage presented with high baseline fibrinogen levels and experienced extensive degradation of coagulable fibrinogen. Overall, patients at greatest risk of systemic fibrinogenolysis tended to be relatively older women with lower body weight. Peak plasma levels of t-PA antigen were weakly correlated with nadir-fibrinogen levels (r = 0.11, p = 0.041) and peak FDP levels (r = 0.12, p = 0.020), and also tended to be higher in older women of lowere body weight. Plasma levels of t-PA antigen were higher in nonoperated patients experiencing 'major' bleeding (3.4 versus 2.2 μg/ml, p = 0.002). These results indicate that changes in coagulation parameters are highly variable in the setting of thrombolytic treatment with t-PA of acute myocardial infarction, precluding their use for predictive monitoring of therapy in individual patients. Nonetheless, the overall pattern of pharmacodynamic behavior or rt-PA within a given population and its correlation with selected major clinical outcomes, particularly with risk of reocclusion and bleeding, will be most useful for the design of alternative administration schemes.",
author = "Stump, {D. C.} and Califf, {R. M.} and Topol, {E. J.} and K. Sigmon and D. Thornton and R. Masek and L. Anderson and D. Collen and O'Neill, {W. W.} and Walton, {J. A.} and Bates, {E. R.} and Ellis, {S. G.} and A. Schork and E. Kline and L. Gorman and R. Worden and B. Pitt and Stack, {R. S.} and Phillips, {H. R.}",
year = "1989",
month = "1",
day = "1",
language = "English",
volume = "80",
pages = "1222--1230",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - Pharmacodynamics of thrombolysis with recombinant tissue-type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction

AU - Stump, D. C.

AU - Califf, R. M.

AU - Topol, E. J.

AU - Sigmon, K.

AU - Thornton, D.

AU - Masek, R.

AU - Anderson, L.

AU - Collen, D.

AU - O'Neill, W. W.

AU - Walton, J. A.

AU - Bates, E. R.

AU - Ellis, S. G.

AU - Schork, A.

AU - Kline, E.

AU - Gorman, L.

AU - Worden, R.

AU - Pitt, B.

AU - Stack, R. S.

AU - Phillips, H. R.

PY - 1989/1/1

Y1 - 1989/1/1

N2 - Coagulation asnalysis was performed on blood samples from 386 patients with acute myocardial infarction drawn before, during, and after a continuous intravenous infusion of 150 mg recombinant tissue-type plasminogen activator (rt-PA) (Activase®). Plasma rt-PA rose to peak levels of 2.1 ± 3.1 μg/ml (mean ± SD). Fibrinogen levels measured by coagulation rate and by sulfite precipitation decreased from baseline levels of 3.0 ± 0.9 and 3.2 ± 1.0 g/l, respectively, to nadir levels of 1,4 ± 0.75 and 1.8 ± 0.92 g/l, respectively, and were associated with peak levels in serum of fibrinogen-degradation products (FDP) of 230 ± 470 μg/ml. Forty percent of patients exprienced a nadir functional-fibrinogen level of less than 1.0 g/l, whereas 20% fell below 0.5 g/l. Nadir fibrinogen levels did not correlate with patency of the infarct-related coronary artery at 90 minutes or with risk of coronary vessel reocclusion within 7-10 days. However, the risk of coronary artery reocclusion was inversely related to the baseline functional fibrinogen level (p = 0.0008), with the magnitude of its drop to nadir level (p = 0.0003) as well as to peak levels of FDP (p = 0.038). Quantitative blood loss correlated with all markers for systemic fibrinogenolysis including nadir fibrinogen level (r = -0.20, p = 0.0011), percent decrease of fibrinogen (r = 0.22, p = 0.001), and peak FDP levels (r = 0.14, p = 0.020). Both patients who experienced intracranial hemorrhage presented with high baseline fibrinogen levels and experienced extensive degradation of coagulable fibrinogen. Overall, patients at greatest risk of systemic fibrinogenolysis tended to be relatively older women with lower body weight. Peak plasma levels of t-PA antigen were weakly correlated with nadir-fibrinogen levels (r = 0.11, p = 0.041) and peak FDP levels (r = 0.12, p = 0.020), and also tended to be higher in older women of lowere body weight. Plasma levels of t-PA antigen were higher in nonoperated patients experiencing 'major' bleeding (3.4 versus 2.2 μg/ml, p = 0.002). These results indicate that changes in coagulation parameters are highly variable in the setting of thrombolytic treatment with t-PA of acute myocardial infarction, precluding their use for predictive monitoring of therapy in individual patients. Nonetheless, the overall pattern of pharmacodynamic behavior or rt-PA within a given population and its correlation with selected major clinical outcomes, particularly with risk of reocclusion and bleeding, will be most useful for the design of alternative administration schemes.

AB - Coagulation asnalysis was performed on blood samples from 386 patients with acute myocardial infarction drawn before, during, and after a continuous intravenous infusion of 150 mg recombinant tissue-type plasminogen activator (rt-PA) (Activase®). Plasma rt-PA rose to peak levels of 2.1 ± 3.1 μg/ml (mean ± SD). Fibrinogen levels measured by coagulation rate and by sulfite precipitation decreased from baseline levels of 3.0 ± 0.9 and 3.2 ± 1.0 g/l, respectively, to nadir levels of 1,4 ± 0.75 and 1.8 ± 0.92 g/l, respectively, and were associated with peak levels in serum of fibrinogen-degradation products (FDP) of 230 ± 470 μg/ml. Forty percent of patients exprienced a nadir functional-fibrinogen level of less than 1.0 g/l, whereas 20% fell below 0.5 g/l. Nadir fibrinogen levels did not correlate with patency of the infarct-related coronary artery at 90 minutes or with risk of coronary vessel reocclusion within 7-10 days. However, the risk of coronary artery reocclusion was inversely related to the baseline functional fibrinogen level (p = 0.0008), with the magnitude of its drop to nadir level (p = 0.0003) as well as to peak levels of FDP (p = 0.038). Quantitative blood loss correlated with all markers for systemic fibrinogenolysis including nadir fibrinogen level (r = -0.20, p = 0.0011), percent decrease of fibrinogen (r = 0.22, p = 0.001), and peak FDP levels (r = 0.14, p = 0.020). Both patients who experienced intracranial hemorrhage presented with high baseline fibrinogen levels and experienced extensive degradation of coagulable fibrinogen. Overall, patients at greatest risk of systemic fibrinogenolysis tended to be relatively older women with lower body weight. Peak plasma levels of t-PA antigen were weakly correlated with nadir-fibrinogen levels (r = 0.11, p = 0.041) and peak FDP levels (r = 0.12, p = 0.020), and also tended to be higher in older women of lowere body weight. Plasma levels of t-PA antigen were higher in nonoperated patients experiencing 'major' bleeding (3.4 versus 2.2 μg/ml, p = 0.002). These results indicate that changes in coagulation parameters are highly variable in the setting of thrombolytic treatment with t-PA of acute myocardial infarction, precluding their use for predictive monitoring of therapy in individual patients. Nonetheless, the overall pattern of pharmacodynamic behavior or rt-PA within a given population and its correlation with selected major clinical outcomes, particularly with risk of reocclusion and bleeding, will be most useful for the design of alternative administration schemes.

UR - http://www.scopus.com/inward/record.url?scp=0024426444&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0024426444&partnerID=8YFLogxK

M3 - Article

VL - 80

SP - 1222

EP - 1230

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 5

ER -