Safety Of Thrombolytic Agents Research Articles

Use of thrombolytic agents to treat neonatal thrombosis in clinical practice.

Among children, neonates have the highest incidence of thrombosis. Thrombolytic agents are used for the management of life and/or organ-threatening thrombosis. Literature on the efficacy and safety of thrombolytic agents in neonates is limited. We reviewed the evidence on dosing, administration, monitoring and treatment duration of tissue plasminogen activator (tPA), streptokinase and urokinase (URK) in neonates (≤ 28days). A systematic literature search was conducted of current databases from inception until 31 March 2021. The initial search yielded 6881 articles and 18 were retained for review. tPA, streptokinase and URK was utilized in 12, seven and four studies on 115, 51 and 16 patients, respectively. The dose range for tPA, streptokinase and URK was 0.01 -0.6 mg/kg/h, 50-2000 and 1000-0 000 units/kg/h, respectively, and treatment duration ranged from 30 min to 30 days. This is the first study to objectively summarize the efficacy and safety of thrombolytic agents in neonates. Overall, thrombolysis was associated with 87.9% complete or partial thrombus resolution and 7.4% recurrence risk. The bleeding risk associated with thrombolytic agents was 23.1% on pooled analysis, which is higher than other anticoagulants. Larger prospective studies are required to determine effective dosing regimens of these therapeutic drugs and further clarify their efficacy and safety. Blood Coagul Fibrinolysis 33:000-000 Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Thrombolytic agents for arterial and venous thromboses in neonates

Clinically symptomatic thromboses are infrequent but serious complications in infants undergoing intensive care. Most are related to central vascular catheters. Symptomatic thrombosis may cause severe morbidity due to irreversible organ damage and also loss of limbs. To assess the efficacy and safety of thrombolytic agents in neonatal arterial and venous thromboses. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2004), MEDLINE (January 1966 to January 2004), EMBASE (January 1980 to January 2004), and CINAHL (January 1982 to January 2004). We also contacted authors of appropriate review articles. Randomised controlled trials (RCT) and quasi RCT comparing thrombolytic agents with either heparin or observation in neonates with symptomatic neonatal arterial and venous thromboses were included. Two reviewers independently searched for eligible trials. No eligible studies were found even after contacting authors of review articles for details of any unpublished trials. No randomised controlled trials (RCT) or quasi-RCT were found. No conclusions could be made as no eligible studies were found. It is time that a randomised controlled trial was performed comparing thrombolytic therapy to heparin therapy to aid neonatologists in the treatment of arterial and venous thromboses.

The fibrinolytic system in children.

The fibrinolytic system comprises a cascade of serine proteinase activation events that culminate in the generation of plasmin and, subsequently, degradation of fibrin. Although all components of the fibrinolytic system are present at birth, plasma concentrations of key components in infants and children differ physiologically from those in adults. Until the age of 6 months, plasma concentrations of plasminogen and alpha (2)-antiplasmin are decreased to 50% and 80% of adult values, respectively, while plasma concentrations of tissue-type plasminogen activator are decreased and plasminogen activator inhibitor-1 are increased throughout childhood. In addition, the rate of plasmin generation in newborns and the overall fibrinolytic activity during childhood are decreased compared with adults. Strong evidence suggests that age-dependent differences in the fibrinolytic system critically influence the effectiveness and safety of thrombolytic agents. In addition, recent studies suggest that impaired fibrinolysis may play an important role in the pathogenesis of several diseases such as venous and arterial diseases and vasculitis, which are associated with both endothelial cell damage and increased thrombotic risk. This article will discuss the ontogenic features of the fibrinolytic system in children and summarize the available information on the effect of developmental fibrinolysis on both the course of specific disease states and the response to thrombolytic therapy in children.

Is thrombolytic therapy safe during active menstruation?

A 39-year-old female presented to the Emergency Department during the fourth day of menstruation and within 2 hours of the onset of chest pain associated with dyspnea, diaphoresis, and emesis. An electrocardiogram showed acute inferior myocardial infarction and serial CPK enzyme levels peaked at 958 IU/L with 9% MB fraction. Along with aspirin and intravenous nitroglycerin, the patient was given thrombolytic therapy consisting of tPA with an initial bolus of 35 units, followed by 65 units infused within 60 minutes together with heparin 5000 units intravenous bolus, and 1000 units/hour maintenance infusion for 5 days. The menses were prolonged 1 day longer than her usual 5 days; however, there was no increase in the amount of bleeding during any day. The hemoglobin dropped from 12.5 G/dl to 11.3 G/dl in the first 6 hours, but remained stable thereafter. This initial drop in hemoglobin was considered a dilutional effect of 1.5 L of normal saline the patient received intravenously during that period. Although no available guidelines exist regarding the safety of thrombolytic agents during active menstruation, this case report and a few others reported in the literature suggest that normal menstruation is not a contraindication to thrombolytic therapy during acute myocardial infarction.

Probing structure-function relationships of tissue-type plasminogen activator by site-specific mutagenesis

Tissue-type plasminogen activator (t-PA), a 65 kDa member of the chymotrypsin family of serine proteases, catalyzes the rate-limiting step in the endogenous fibrinolytic cascade: conversion of the zymogen plasminogen into the active enzyme plasmin.‘-” Plasmin, a serine protease of relatively broad specificity, efficiently degrades the fibrin that forms the meshwork of a thrombus or blood clot.‘-3 The fibrinolytic cascade, therefore, provides an important counterbalance in vivo to the blood coagulation cascade. Appreciation that inappropriate thrombosis was the focal event in the initiation of acute myocardial infarction, and the demonstration that timely administration of thrombolytic agents could restore patency to occluded coronary arteries sparked great interest in thrombolytic therapy, the endogenous fibrinolytic system and, in particular, the plasminogen activators. Current thrombolytic therapy achieves lysis of stable coronary thrombi through the intravenous administration of plasminogen activators, usually either human t-PA or the bacterial protein, streptokinase.‘.” The evidence that thrombolytic therapy is capable of rapidly lysing thrombi without undue risk of hemorrhage is now convincing; numerous studies and clinical trials have confirmed both the efficacy and the safety of thrombolytic agents in the treatment of patients with an evolving myocardial infarction.4-‘2 t-PA is synthesized and secreted by vascular endothelial cells.’ 3-16 The amino acid sequence of the human t-PA precursor, originally deduced from the nucleotide sequence of cloned cDNAs”,‘~ and subsequently confirmed by amino acid sequencing of the purified proteinI consists of 563 amino acids. As this precursor is transported along the secretory pathway, oligosaccharide groups are added at three positions (Asn 117, Asn 184, and Asn 448), and both a hydrophobic signal sequence and a hydrophilic prosequence are removed by endopeptidic cleavage. ‘9-2’ The resulting 527 amino

Comparative safety of thrombolytic agents

Three available thrombolytic agents, streptokinase, alteplase, and anistreplase, have been shown to have similar effects on preservation of left ventricular function and mortality reduction after acute myocardial infarction (AMI). The agents are, however, quite different with respect to their safety profiles. Clinical trials to date suggest that alteplase (tissue plasminogen activator) or anistreplase administration is associated with a high incidence of cerebral hemorrhage. In contrast, streptokinase is associated with a low rate of cerebral hemorrhage. Streptokinase and anistreplase are associated with a higher risk of allergic reaction when compared with alteplase. Hypotension is also more common with streptokinase and anistreplase, but occurs significantly with alteplase as well. Alteplase is associated with a lower reinfarction rate when compared with streptokinase and anistreplase. The Third International Study of Infarct Survival (ISIS-3), a direct comparison of 3 thrombolytic agents (streptokinase, anistreplase, and duteplase), may provide some insight regarding the safety of these agents. Because these agents have been shown to be equally effective, selection of an appropriate agent for an individual patient may depend more on assessment of the likelihood of an adverse event or other factors, such as cost or convenience of administration, rather than assessment of the probability of greater benefit with a particular agent.