Argatroban therapy in pediatric patients requiring nonheparin anticoagulation: An open‐label, safety, efficacy, and pharmacokinetic study

Young, Guy; Boshkov, Lynn K.; Sullivan, Janice E.; Raffini, Leslie; Cox, Donna S.; Boyle, D.A.; Kallender, Howard; Tarka, Elizabeth; Soffer, Joseph; Hursting, Marcie J.

doi:10.1002/pbc.22852

Cited by 67 publications

(45 citation statements)

References 31 publications

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“…Given its significant deleterious outcomes, if suspected, all heparin should be stopped and a non-heparin alternative, such as a direct thrombin inhibitor (DTI), should be started until HIT is ruled out (48). Argatroban is the only DTI that has been prospectively studied in pediatric patients with HIT, and dosing guidelines are now included in the prescribing information (49, 50). …”

Section: Morbidity/mortalitymentioning

confidence: 99%

Neonatal Venous Thromboembolism

Haley

2017

Front. Pediatr.

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Neonates are the pediatric population at highest risk for development of venous thromboembolism (VTE), and the incidence of VTE in the neonatal population is increasing. This is especially true in the critically ill population. Several large studies indicate that the incidence of neonatal VTE is up almost threefold in the last two decades. Central lines, fluid fluctuations, sepsis, liver dysfunction, and inflammation contribute to the risk profile for VTE development in ill neonates. In addition, the neonatal hemostatic system is different from that of older children and adults. Platelet function, pro- and anticoagulant proteins concentrations, and fibrinolytic pathway protein concentrations are developmentally regulated and generate a hemostatic homeostasis that is unique to the neonatal time period. The clinical picture of a critically ill neonate combined with the physiologically distinct neonatal hemostatic system easily fulfills the criteria for Virchow’s triad with venous stasis, hypercoagulability, and endothelial injury and puts the neonatal patient at risk for VTE development. The presentation of a VTE in a neonate is similar to that of older children or adults and is dependent upon location of the VTE. Ultrasound is the most common diagnostic tool employed in identifying neonatal VTE, but relatively small vessels of the neonate as well as frequent low pulse pressure can make ultrasound less reliable. The diagnosis of a thrombophilic disorder in the neonatal population is unlikely to change management or outcome, and the role of thrombophilia testing in this population requires further study. Treatment of neonatal VTE is aimed at reducing VTE-associated morbidity and mortality. Recommendations for treating, though, cannot be extrapolated from guidelines for older children or adults. Neonates are at risk for bleeding complications, particularly younger neonates with more fragile intracranial vessels. Developmental alterations in the coagulation proteins as well as unique pharmacokinetics must also be taken into consideration when recommending VTE treatment. In this review, epidemiology of neonatal VTE, pathophysiology of neonatal VTE with particular attention to the developmental hemostatic system, diagnostic evaluations of neonatal VTE, and treatment guidelines for neonatal VTE will be reviewed.

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Section: Morbidity/mortalitymentioning

confidence: 99%

Neonatal Venous Thromboembolism

Haley

2017

Front. Pediatr.

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“…In a multicenter, single arm, open-label study, of 18 patients (range 1.6 weeks to 16 years), argatroban was employed for either a suspicion of or being at risk for HIT, or other conditions requiring non-heparin anticoagulation [56] without major thrombotic complications but with two major bleeding events. However argatroban dose was 1 mg/kg/min, with therapeutic APTTs (1.5-3Â baseline) achieved within 7 h and pharmacometric analyses demonstrated the optimal initial argatroban dose in children is 0.75 mg/kg/min (if normal hepatic function), with dose reduction to 0.2 mg/kg/min in hepatic impairment.…”

Section: Hit In Childrenmentioning

confidence: 99%

Current management of heparin-induced thrombocytopenia

Cosmi

2015

Expert Review of Hematology

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Heparin-induced thrombocytopenia (HIT) is an immune adverse reaction to heparin (both unfractionated and low-molecular-weight), which is mediated by the formation of IgG antibodies against platelet factor 4-heparin complexes. The IgG/platelet factor 4 immunocomplexes activate platelets with resulting thrombocytopenia, which is not associated with bleeding, but with paradoxical life-threatening thrombotic complications, for coagulation activation. HIT diagnosis requires the assessment of pre-test clinical probability in combination with the measurement of platelet activating antibodies against platelet factor 4-heparin complexes with immunological and functional assays. When HIT is diagnosed, any form of heparin should be stopped and a non-heparin alternative anticoagulant should be started. Argatroban and danaparoid are currently the only drugs licensed for HIT, with different country availability. Bivalirudin is an option in cardiac surgery and procedures in HIT patients.

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“…Continuous infusion of argatroban should be started at 0.75-1 lg/kg/min, with dose titration based on PTT (target 60-85 s) from 2 h after initiation [5] Bivalirudin should be administered as a bolus dose of 0.125 mg/kg, followed by a continuous infusion of 0.125 mg/kg/h and dose titration based on PTT (target 60-85 s) from 3-4 h after initiation [6,7] ATIII antithrombin III, CYP cytochrome P450, DTI direct thrombin inhibitor, HIT heparin-induced thrombocytopenia, INR international normalized ratio, LMWH low molecular weight heparin, PTT partial thromboplastin time, UFH unfractionated heparin paediatric patients, with LMWH being the most frequently used due to its predictable pharmacokinetic properties (Table 1). UFH, warfarin and argatroban are the only anticoagulants with any (albeit very limited) labelling information regarding their use in paediatric patients in the USA [1].…”

Section: Direct Thrombin Inhibitorsmentioning

confidence: 99%

Consider dosing, monitoring and complications when using anticoagulants to treat acute venous thromboembolism in paediatric patients

Writers

2015

Drugs Ther Perspect

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Appropriate dosing, routine monitoring and the risks of complications are important considerations when treating acute venous thromboembolism (VTE) in paediatric patients. Due to the lack of high-quality evidence, the use of anticoagulants in paediatric patients is largely based on extrapolation from adult data. Age-dependent differences in haemostasis and drug metabolism, particularly in neonates, makes this approach sub-optimal.

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Argatroban therapy in pediatric patients requiring nonheparin anticoagulation: An open‐label, safety, efficacy, and pharmacokinetic study

Cited by 67 publications

References 31 publications

Neonatal Venous Thromboembolism

Neonatal Venous Thromboembolism

Current management of heparin-induced thrombocytopenia

Consider dosing, monitoring and complications when using anticoagulants to treat acute venous thromboembolism in paediatric patients

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