Thrombolytic Therapy: Current Status

Marder, Victor J.; Sherry, Sol

doi:10.1056/nejm198806163182406

Cited by 244 publications

(106 citation statements)

References 99 publications

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“…Potent thrombolytic agents, such as rt-PA, have permitted effective thrombolysis in occluded arteries, particularly for myocardial salvage in acute myocardial infarction [5]. However, a hemorrhagic event, such as cerebral or gastrointestinal bleeding, can occur during or after thrombolysis, causing substantial complications [6][7][8][9]. Adjuvant therapies that lower the dose of rt-PA or increase its efficacy would represent a significant breakthrough.…”

Section: Introductionmentioning

confidence: 99%

Ultrasound-enhanced tissue plasminogen activator thrombolysis in an in vitro porcine clot model

Holland

Vaidya

Datta

et al. 2008

Thrombosis Research

100

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Section: Introductionmentioning

confidence: 99%

Ultrasound-enhanced tissue plasminogen activator thrombolysis in an in vitro porcine clot model

Holland

Vaidya

Datta

et al. 2008

Thrombosis Research

100

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“…Potency in vivo, measured in the rabbit jugular vein thrombus model, increased by 29-fold. Thus, conjugation to a fibrin-specific Fab' appears to increase the fibrin affinity and fibrinolytic potency of scu-PA. (Circulation 1990:81;1974-1980 W hen plasminogen activator therapy is instituted within 4-6 hours of the onset of symptoms of acute myocardial infarction, there is a significant reduction in morbidity and mortality.1 2 The first generation of plasminogen activators, streptokinase and urokinase, are effective but lack. fibrin and hence clot specificity.…”

mentioning

confidence: 99%

Conjugation to antifibrin Fab' enhances fibrinolytic potency of single-chain urokinase plasminogen activator.

et al. 1990

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Single-chain urokinase plasminogen activator (scu-PA) that had been modified with Nsuccinimidyl-3-(2-pyridyldithio)propionate was covalently linked by disulfide bonds to the Fab' of a monoclonal antibody specific for the P-chain of fibrin (antibody 59D8). scu-PA-59D8 Fab' conjugate was separated from free scu-PA and two-chain urokinase coupled to 59D8 Fab' by two-step affinity chromatography. First, the reaction mixture was chromatographed on a column containing Sepharose linked to the peptide that had been used as immunogen for antibody 59D8; scu-PA-59D8 Fab' conjugate and unconjugated 59D8 Fab' were retained but not unconjugated scu-PA. Then, the eluate from the peptide-Sepharose column was chromatographed on a column containing Sepharose linked to benzamidine, which acts as a ligand for two-chain urokinase. The molecular weight of the scu-PA-59D8 Fab' conjugate was approximately 100 kDa when electrophoresed on a nonreducing sodium dodecylsulfate-polyacrylamide gel. Enzymatic assay after purification revealed that more than 97% of the scu-PA present in the conjugate retained the single-chain form. The Fab' portion of the conjugate functioned in a manner indistinguishable from that of native antibody 59D8. In an in vitro assay for lysis of fibrin monomer, the fibrinolytic potency of scu-PA-59D8 Fab' was 33-fold more than that of tissue plasminogen activator (p<0.001), 230-fold more than that of unconjugated scu-PA (p<0.0001), and 420-fold more than that of urokinase (p<0.0001). In a human plasma clot assay, scu-PA-59D8 Fab' was significantly more potent than native scu-PA in clot lysis and consumed less fibrinogen at equipotent fibrinolytic concentrations. Potency in vivo, measured in the rabbit jugular vein thrombus model, increased by 29-fold. Thus, conjugation to a fibrin-specific Fab' appears to increase the fibrin affinity and fibrinolytic potency of scu-PA. (Circulation 1990:81;1974-1980 W hen plasminogen activator therapy is instituted within 4-6 hours of the onset of symptoms of acute myocardial infarction, there is a significant reduction in morbidity and mortality.1 2 The first generation of plasminogen activators, streptokinase and urokinase, are effective but lack. fibrin and hence clot specificity. Secondgeneration plasminogen activators tissue-type plasminogen activator (t-PA) and single-chain urokinase plasminogen activator (scu-PA) are relatively fibrin One approach to improving the specificity of currently available thrombolytic agents is to increase their fibrin affinity by conjugation to an antifibrin antibody. We have studied conjugates between antifibrin monoclonal antibody 59D8 and urokinase8,9 and between 59D8 and t-PA.l0,1l Conjugation markedly enhances the thrombolytic potency of the two plasminogen activators, both in vitro and in vivo.scu-PA is perhaps the most promising plasminogen activator to which direct fibrin specificity could be added. Native scu-PA is fibrin selective, but this selectivity derives from the activation of fibrin-bound plasminogen. Although the mechanism of activ...

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“…O ponto importante com relação ao uso das medicações fibrinolíticas são suas complicações 7,[55][56][57][58] . Viuse, acima, que as complicações decorrentes do uso da estreptoquinase são difíceis de ser previstas mediante avaliação laboratorial do paciente no transcorrer da sua infusão endovenosa.…”

Section: Discussionunclassified

O uso da estreptoquinase no tratamento da oclusão arterial aguda pós-cateterização da artéria femoral em crianças com menos de 10 kg

et al. 2007

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CONTEXTO: O tratamento da oclusão arterial aguda em menores de 5 kg tem constituído tema de discussão. OBJETIVOS: Avaliar o tratamento do quadro da oclusão arterial aguda pós-cateterismo da artéria femoral em crianças com menos de 10 kg com o uso de heparina isolada e também associada com estreptoquinase, e comparar os resultados do exame físico (como diagnóstico), da reversão da oclusão arterial, de complicações e de exames laboratoriais nos dois métodos MÉTODOS: Trinta casos de oclusão da artéria femoral foram identificados em 1.583 cateterismos em crianças no Instituto de Cardiologia de Porto Alegre, entre 1992 e 2000. Os pacientes foram divididos em dois grupos: um usou apenas heparina (14 casos), e o outro usou heparina associada com estreptoquinase (16 casos). Os exames laboratoriais (tempo de protrombina, tempo de tromboplastina parcial ativado e fibrinogênio) coletados antes e durante a infusão intravenosa foram avaliados estatisticamente, assim como o tempo de uso da medicação, as complicações e os resultados. RESULTADOS: O exame físico mostrou-se método fidedigno para avaliar a oclusão; no grupo que utilizou a associação de heparina e estreptoquinase, houve a resolução de 87% dos casos de oclusão arterial, e a principal complicação foi sangramento no sítio de punção em 56,3% dos pacientes. Os resultados apresentaram p < 0,05. Os exames laboratoriais não tiveram significado estatístico. CONCLUSÃO: A estreptoquinase associada com a heparina é mais efetiva do que a heparina isolada no tratamento da oclusão arterial aguda da artéria femoral pós-cateterismo, tanto que sua associação apresenta uma redução do risco relativo de 88% em relação à heparina isolada.

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Thrombolytic Therapy: Current Status

Cited by 244 publications

References 99 publications

Ultrasound-enhanced tissue plasminogen activator thrombolysis in an in vitro porcine clot model

Ultrasound-enhanced tissue plasminogen activator thrombolysis in an in vitro porcine clot model

Conjugation to antifibrin Fab' enhances fibrinolytic potency of single-chain urokinase plasminogen activator.

O uso da estreptoquinase no tratamento da oclusão arterial aguda pós-cateterização da artéria femoral em crianças com menos de 10 kg

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