Tissue plasminogen activator for the treatment of thromboembolism in infants and children

doi:10.1016/S0022-3476(05)82170-5

The Journal of Pediatrics

Volume 118, Issue 3, March 1991, Pages 467-472

https://doi.org/10.1016/S0022-3476(05)82170-5 Get rights and content

We report our experience with the use of tissue plasminogen activator to treat 12 infants and children with various thromboembolic states after conventional thrombolytic agents had failed. The dosage range was between 0.1 to 0.5 mg/kg per hour. Complete clot dissolution occurred in seven cases after 2 hours to 3 days of therapy. Partial clot dissolution and clinical improvement were noted in another four patients. Bleeding complications were noted in 6 of the 12 patients and included bruising, oozing from various venipuncture sites, and bleeding; these complications were controlled by clinically available means. In all cases with bleeding the dose rate was in the higher range (0.46 to 0.50 mg/kg per hour). In one patient, restlessness, agitation, and screaming were noted during administration of tissue plasminogen activator and when it was reinstituted. We conclude that tissue plasminogen activator is effective in inducing clot lysis in children. Because the effective dose appears to overlap with those causing bleeding, we recommend that a dose of 0.1 mg/kg per hour be started and increased gradually if clot dissolution does not occur, with close monitoring for bleeding.

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Cited by (119)

Clinical use of tissue plasminogen activator for systemic thrombolysis in dogs and cats
2022, Journal of Veterinary Cardiology
Citation Excerpt :
In children, a dose of 0.1 mg/kg/hr is recommended with close monitoring of clot resolution, with a dose range between 0.1 and 0.5 mg/kg/hr [42]. Bleeding complications are reported at the higher end of the dose and should be able to be clinically controlled without need to stop the infusion [42]. Although constant rate infusions were not used, the clinical practice reported in our study included small amounts of tPA that were given several times while monitoring clot resolution and side-effects, a similar concept to a constant rate infusion, and that is based on the short half-life of tPA [43].
Systemic administration of tissue plasminogen activator (tPA) is seldomly reported in dogs and cats.
Client-owned animals receiving tPA (2010–2020).
Medical records of dogs and cats receiving tPA for distant known/suspected thrombus were reviewed. Fourteen dog visits (24 injections) and five cat visits (six injections) were included.
Canine known/suspected thrombus included pulmonary thromboembolism (n=6), intracardiac thrombus (n=4), aortic thrombus (n=1), cranial vena cava thrombus (n=2), and femoral and iliac veins thrombus (n=1). Various canine primary diseases were represented, but open-heart surgery was the most common cause. Median time between diagnosis/suspicion of thrombus and tPA injection was 24.5 h (range, 3–150 h). Mean total tPA dose was 1.0±0.78 mg/kg.
Clinical improvement occurred in 93% of dogs. Non-fatal complications were reported in 14% of dogs. Dogs’ survival to discharge was 78.6% without identifiable non-survivor characteristics. Feline known/suspected thrombus included unilateral feline aortic thromboembolism (FATE) (n=2), bilateral FATE (n=2), and right renal artery thrombus. Feline primary diseases included cardiomyopathy (n=5). Median time between diagnosis/suspicion of thrombus and tPA injection was 4 h (range, 2–17 h) and median total tPA dose was 1.0 mg/kg (range, 0.6–1.4 mg/kg).Clinical improvement occurred during 40% of the visits. All cats (n=3) with acute kidney injury (AKI) at admission developed worsening AKI and reperfusion injury. Of the remaining two visits, one developed a non-fatal AKI. Cats’ survival to discharge was 40%.
Systemic thrombolysis with tPA seems to be effective and safe in dogs. More investigation is needed in cats.
Tissue Plasminogen Activator Use in Children: Bleeding Complications and Thrombus Resolution
2016, Journal of Pediatrics
To review our institutional experience with tissue plasminogen activator (tPA) to determine outcomes related to bleeding complications and thrombus resolution.
We performed a retrospective review of all patients who received systemic tPA for thrombolysis. Data points included location of thrombus, initial and maximum tPA dose, and duration of tPA. The primary endpoint was bleeding complication.
Between 2005 and 2014, 46 patients received systemic tPA for thrombolysis: 17 (37%) were patients with a primary cardiac diagnosis, there were 17 (37%) hematology/oncology patients, and 12 (26%) patients with noncardiac, nonhematology/oncology diagnoses. The indication for tPA was central venous thrombus (n = 23), pulmonary artery thrombus (n = 9), and cardiac or aortic thrombus (n = 14). Bleeding complications occurred in 15 patients (33%). Median initial tPA dose in the bleeding complication group was 0.10 mg/kg/h vs 0.03 mg/kg/h in the group without bleeding complication group (P = .01). Cardiac patients experienced more bleeding complications (P = .01). Multivariate analysis indicated that dose of tPA (P = .01) and diagnostic category (P < .01) were associated with bleeding complication. Complete thrombus resolution occurred in 21 patients, partial in 10 patients, and no resolution in 15 patients. Complete resolution of thrombus was not associated with diagnosis, thrombus location, tPA dose, or duration.
Cardiac patients appear to be at highest risk of bleeding complication; bleeding complications were associated with higher doses of tPA, and cardiac patients were the cohort who received the highest doses of tPA. Higher tPA doses are associated with increased risk of bleeding complication but are not associated with successful thrombus resolution.
Antithrombotic therapy in neonates and children: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines
2012, Chest
Neonates and children differ from adults in physiology, pharmacologic responses to drugs, epidemiology, and long-term consequences of thrombosis. This guideline addresses optimal strategies for the management of thrombosis in neonates and children.
The methods of this guideline follow those described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
We suggest that where possible, pediatric hematologists with experience in thromboembolism manage pediatric patients with thromboembolism (Grade 2C). When this is not possible, we suggest a combination of a neonatologist/pediatrician and adult hematologist supported by consultation with an experienced pediatric hematologist (Grade 2C). We suggest that therapeutic unfractionated heparin in children is titrated to achieve a target anti-Xa range of 0.35 to 0.7 units/mL or an activated partial thromboplastin time range that correlates to this anti-Xa range or to a protamine titration range of 0.2 to 0.4 units/mL (Grade 2C). For neonates and children receiving either daily or bid therapeutic low-molecular-weight heparin, we suggest that the drug be monitored to a target range of 0.5 to 1.0 units/mL in a sample taken 4 to 6 h after subcutaneous injection or, alternatively, 0.5 to 0.8 units/mL in a sample taken 2 to 6 h after subcutaneous injection (Grade 2C).
The evidence supporting most recommendations for antithrombotic therapy in neonates and children remains weak. Studies addressing appropriate drug target ranges and monitoring requirements are urgently required in addition to site- and clinical situation-specific thrombosis management strategies.
Efficacy of Local Instillation of Recombinant Tissue Plasminogen Activator for Restoring Occluded Central Venous Catheters in Neonates
2010, Journal of Pediatrics
To evaluate the efficacy of local instillation of tissue plasminogen activator (tPA) for restoring function to occluded central venous catheters (CVCs) in the neonatal population.
This was a retrospective review of patients admitted to the neonatal intensive care unit during September 2000 to April 2006 who received instillation of tPA for occluded CVCs.
Among 18 infants who received tPA for occluded CVCs, gestational age at birth was 32.5 weeks, birth weight was 1550 g, and gestational age at tPA administration was 39 weeks, with 4 neonates ≤32 weeks' gestational age at tPA administration; age at tPA use was 39 days (medians reported). Ten of 18 (55%) of CVC occlusions were successfully opened after using tPA. No bleeding complications of tPA were noted, including increased or new-onset intraventricular hemorrhage, overt bleeding, or changes in INR or partial thromboplastin time attributed to tPA use. Three patients (16.5%) had bacteremia within 7 days of tPA administration, and no catheter ruptures occurred.
Local instillation of tPA was successful in restoring function to occluded CVCs in a significant proportion of neonates, although success rates were lower than that reported in populations of older age. Despite the vulnerability of neonates to the potential complications of tPA, no major complications were detected even among premature infants.
Massive Pulmonary Embolism in Children
2010, Journal of Pediatrics
Citation Excerpt :
In addition, we performed a PubMed search from January 1990 to December 2008 to identify all reports of massive PE in children <19 years old (key words: pediatric, pulmonary embolism, massive PE, death, shock). We chose this time period because reports of thrombolysis for pediatric PE became more frequent in the early 1990s,4–6 and we wished to include the potential use of that therapy in our review. In addition, noninvasive diagnostic testing for PE improved during this time, such that ventilation/perfusion lung scan and chest computed tomography were recognized as acceptable diagnostic modalities.1,7
Acute neonatal arterial occlusion: is thrombolysis safe and effective?
2008, Journal of Pediatric Surgery
Citation Excerpt :
It exerts its effects by initially binding to clot-bound fibrin. This complex produces plasmin at the site of the clot [13], resulting in dissolution. The use of t-PA in adult practice for the treatment of pulmonary embolism, deep vein thrombosis, and acute myocardial infarction has been extensively reported.
We report our experience of the management of arterial occlusion in the newborn.
A case note review was carried out after ethical approval. Doppler ultrasonography confirmed the occlusion. Thrombolysis was the primary intervention. Surgery was used selectively. A good outcome was one without tissue loss or functional impairment or minimal tissue loss without functional impairment. Data are presented as medians with ranges.
Ten patients (9 male; median gestational age, 35.5 weeks [range, 28-39 weeks]) presented on day 1 (range, 1-8 days). Initial management included systemic tissue plasminogen activator (8 patients) and surgery (2 infants in whom thrombolysis was contraindicated). Improvement was noted in 7 of 8 infants treated medically and in both who underwent surgery. Three infants had significant tissue loss. Outcome at 29 months (range, 1.3-95.4 months) was good in the remaining 7.
A multidisciplinary approach, thrombolysis and selective surgery achieved tissue preservation and function in the majority while minimizing complications. Early referral to centers with multidisciplinary teams is recommended.

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^*: Dr. Koren is a Career Scientist of the Ontario Ministry of Health.

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References (29)

Fibrinolysis by tissue plasminogen activator in a child with pulmonary embolism

J Pediatr

Heparinization for prevention of thrombosis following pediatric percutaneous arterial catheterization

Pediatr Cardiol

Treatment of postvitrectomy fibrin formation with intracellular tissue plasminogen activator

Arch Ophthalmol

Thrombolytic treatment with recombinant tissue type plasminogen activator in patients with massive pulmonary embolism

Ann Intern Med

Update for the thrombolysis in myocardial infarction trial

J Am Coll Cardiol

Intravenous recombinant tissue plasminogen activator in patients with acute myocardial infarction: a report from NHLB-thrombolysis in myocardial infarction (TIMI)

Circulation

Fibrinolytic activator and inhibitor in terminal renal insufficiency and in anephric patients

Thromb Haemost

Latent tissue plasminogen activator produced by human endothelial cells in culture: evidence for an enzyme-inhibitor complex

Proc Natl Acad Sci USA

Cloning and expression of human tissue type plasminogen activator cDNA in E. coli

Nature

Tissue plasminogen activator: a new thrombolytic agent

Clin Pharm

Alteplase: a tissue plasminogen activator for acute myocardial infarction

Drug Intell Clin Pharm

Thrombolytic therapy in acute myocardial infarction. Part I

Med Clin North Am

Thrombolytic therapy in acute myocardial infarction. Part II. rt-PA

Med Clin North Am

Thrombolytic therapy: current status

Parts I and II

Thrombolytic therapy: current status

Parts I and II

Cited by (119)

Clinical use of tissue plasminogen activator for systemic thrombolysis in dogs and cats

Tissue Plasminogen Activator Use in Children: Bleeding Complications and Thrombus Resolution

Antithrombotic therapy in neonates and children: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines

Efficacy of Local Instillation of Recombinant Tissue Plasminogen Activator for Restoring Occluded Central Venous Catheters in Neonates

Massive Pulmonary Embolism in Children

Acute neonatal arterial occlusion: is thrombolysis safe and effective?