Differential effects of activation of prothrombin by streptokinase compared with urokinase and tissue-type plasminogen activator (t-PA)

Paul R. Eisenberg, Joseph P. Miletich, Burton E. Sobel, Allan S Jaffe

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

We have previously reported paradoxical prothrombotic effects manifest by elevations of fibrinopeptide A (FPA) after administration of streptokinase to patients with acute myocardial infarction. To characterize mechanisms responsible and their dependence on streptokinase (SK) as opposed to other activators of the fibrinolytic system, the present study was performed to compare effects of streptokinase, tissue-type plasminogen activator (t-PA), and urokinase on plasma and on purified prothrombin in concentrations similar to those achieved pharmacologically. The effects of plasmin were assessed to determine the extent to which the elevations of FPA seen could be attributed to activation of plasminogen. Elevations of FPA were observed after incubation of each of the activators with citrated plasma at 37°C for 60 minutes. However, they were most marked with streptokinase (64.5 ± 4.6 pmol FPA/ml (mean ± SE) with 100 IU SK/ml, and 77.6 ± 5.0 pmol/ml with 500 IU SK/ml). Elevations of FPA induced by streptokinase were attenuated by 100 IU/ml heparin [15.2 ± 1.9 pmol/ml after 100 IU of SK (p < 0.001 compared with results with streptokinase without heparin)). Human plasmin, 2.5 CTA/ml, caused changes similar to those induced by streptokinase. The minimal elevations of FPA induced by t-PA or urokinase (< 10 pmol/ml without heparin) were not significantly attenuated by heparin. Incubation of barium citrate adsorbed plasma (vitamin K factor depleted) with streptokinase markedly attenuated elevation of FPA. Addition of prothrombin (1.5 μM) and streptokinase (100 IU/ml) to the barium citrate adsorbed plasma elicited elevations of FPA similar to those induced by streptokinase in citrated plasma. Amidolytic activity with the "thrombin" substrate H-D-phenylalanyl-Lpipecolyl-L-arginine-p-nitroanilide dihydrochloride (S-2238) was evident when streptokinase, plasminogen (0.24 μM), and prothrombin (1.5 μM) were incubated in buffer. Thus, concentrations of streptokinase that are low in terms of therapeutic blood levels activate prothrombin in plasma, likely due to activation of plasminogen. Neither tissue-type plasminogen activator nor urokinase in pharmacologically comparable concentrations increase thrombin activity appreciably perhaps because of less intense activation of plasminogen. Consideration of the prothrombotic effects observed maybe relevant to selection of specific agents for therapeutic thrombolysis, to appropriate titration of dose, and to the need for the use of heparin conjointly with particular activators of the fibrinolytic system such as streptokinase.

Original languageEnglish (US)
Pages (from-to)707-717
Number of pages11
JournalThrombosis Research
Volume50
Issue number5
DOIs
StatePublished - Jun 1 1988
Externally publishedYes

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Streptokinase
Urokinase-Type Plasminogen Activator
Prothrombin
Tissue Plasminogen Activator
Fibrinopeptide A
Plasminogen
Heparin
Fibrinolysin
Barium
Citric Acid
Thrombin
S 2238
Vitamin K
Thrombolytic Therapy

Keywords

  • fibrinopeptide A
  • plasminogen activators
  • prothrombin
  • thrombolysis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Hematology

Cite this

Differential effects of activation of prothrombin by streptokinase compared with urokinase and tissue-type plasminogen activator (t-PA). / Eisenberg, Paul R.; Miletich, Joseph P.; Sobel, Burton E.; Jaffe, Allan S.

In: Thrombosis Research, Vol. 50, No. 5, 01.06.1988, p. 707-717.

Research output: Contribution to journalArticle

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AU - Miletich, Joseph P.

AU - Sobel, Burton E.

AU - Jaffe, Allan S

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N2 - We have previously reported paradoxical prothrombotic effects manifest by elevations of fibrinopeptide A (FPA) after administration of streptokinase to patients with acute myocardial infarction. To characterize mechanisms responsible and their dependence on streptokinase (SK) as opposed to other activators of the fibrinolytic system, the present study was performed to compare effects of streptokinase, tissue-type plasminogen activator (t-PA), and urokinase on plasma and on purified prothrombin in concentrations similar to those achieved pharmacologically. The effects of plasmin were assessed to determine the extent to which the elevations of FPA seen could be attributed to activation of plasminogen. Elevations of FPA were observed after incubation of each of the activators with citrated plasma at 37°C for 60 minutes. However, they were most marked with streptokinase (64.5 ± 4.6 pmol FPA/ml (mean ± SE) with 100 IU SK/ml, and 77.6 ± 5.0 pmol/ml with 500 IU SK/ml). Elevations of FPA induced by streptokinase were attenuated by 100 IU/ml heparin [15.2 ± 1.9 pmol/ml after 100 IU of SK (p < 0.001 compared with results with streptokinase without heparin)). Human plasmin, 2.5 CTA/ml, caused changes similar to those induced by streptokinase. The minimal elevations of FPA induced by t-PA or urokinase (< 10 pmol/ml without heparin) were not significantly attenuated by heparin. Incubation of barium citrate adsorbed plasma (vitamin K factor depleted) with streptokinase markedly attenuated elevation of FPA. Addition of prothrombin (1.5 μM) and streptokinase (100 IU/ml) to the barium citrate adsorbed plasma elicited elevations of FPA similar to those induced by streptokinase in citrated plasma. Amidolytic activity with the "thrombin" substrate H-D-phenylalanyl-Lpipecolyl-L-arginine-p-nitroanilide dihydrochloride (S-2238) was evident when streptokinase, plasminogen (0.24 μM), and prothrombin (1.5 μM) were incubated in buffer. Thus, concentrations of streptokinase that are low in terms of therapeutic blood levels activate prothrombin in plasma, likely due to activation of plasminogen. Neither tissue-type plasminogen activator nor urokinase in pharmacologically comparable concentrations increase thrombin activity appreciably perhaps because of less intense activation of plasminogen. Consideration of the prothrombotic effects observed maybe relevant to selection of specific agents for therapeutic thrombolysis, to appropriate titration of dose, and to the need for the use of heparin conjointly with particular activators of the fibrinolytic system such as streptokinase.

AB - We have previously reported paradoxical prothrombotic effects manifest by elevations of fibrinopeptide A (FPA) after administration of streptokinase to patients with acute myocardial infarction. To characterize mechanisms responsible and their dependence on streptokinase (SK) as opposed to other activators of the fibrinolytic system, the present study was performed to compare effects of streptokinase, tissue-type plasminogen activator (t-PA), and urokinase on plasma and on purified prothrombin in concentrations similar to those achieved pharmacologically. The effects of plasmin were assessed to determine the extent to which the elevations of FPA seen could be attributed to activation of plasminogen. Elevations of FPA were observed after incubation of each of the activators with citrated plasma at 37°C for 60 minutes. However, they were most marked with streptokinase (64.5 ± 4.6 pmol FPA/ml (mean ± SE) with 100 IU SK/ml, and 77.6 ± 5.0 pmol/ml with 500 IU SK/ml). Elevations of FPA induced by streptokinase were attenuated by 100 IU/ml heparin [15.2 ± 1.9 pmol/ml after 100 IU of SK (p < 0.001 compared with results with streptokinase without heparin)). Human plasmin, 2.5 CTA/ml, caused changes similar to those induced by streptokinase. The minimal elevations of FPA induced by t-PA or urokinase (< 10 pmol/ml without heparin) were not significantly attenuated by heparin. Incubation of barium citrate adsorbed plasma (vitamin K factor depleted) with streptokinase markedly attenuated elevation of FPA. Addition of prothrombin (1.5 μM) and streptokinase (100 IU/ml) to the barium citrate adsorbed plasma elicited elevations of FPA similar to those induced by streptokinase in citrated plasma. Amidolytic activity with the "thrombin" substrate H-D-phenylalanyl-Lpipecolyl-L-arginine-p-nitroanilide dihydrochloride (S-2238) was evident when streptokinase, plasminogen (0.24 μM), and prothrombin (1.5 μM) were incubated in buffer. Thus, concentrations of streptokinase that are low in terms of therapeutic blood levels activate prothrombin in plasma, likely due to activation of plasminogen. Neither tissue-type plasminogen activator nor urokinase in pharmacologically comparable concentrations increase thrombin activity appreciably perhaps because of less intense activation of plasminogen. Consideration of the prothrombotic effects observed maybe relevant to selection of specific agents for therapeutic thrombolysis, to appropriate titration of dose, and to the need for the use of heparin conjointly with particular activators of the fibrinolytic system such as streptokinase.

KW - fibrinopeptide A

KW - plasminogen activators

KW - prothrombin

KW - thrombolysis

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