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A preterm female infant was born at 27+1 weeks of gestational age (GA) (birth weight 690 g) and an umbilical vein catheter (UVC) was placed. The tip was located, using chest X-ray (CXR), at T6 thoracic spine level, inside the right atrium of the heart, thus was pulled back and subsequently identified at correct position on CXR. On day 10, routine echocardiography showed a right atrial mass consistent with clot (sized 4.8×4.8 mm) (online supplemental video 1). The UVC presented no continuity with the clot and was well placed. Thus, it was removed and replaced with a central venous catheter. Low molecular weight heparin (LMWH) (enoxaparin) was started at a low dose (100 IU/kg two times per day) but the clot increased in size and was oscillating near the orifice of the tricuspid valve. Unfractionated heparin infusion at 20 IU/kg/hour was started. However, the thrombus continued to increase in size reaching the tricuspid valve and protruded in the right ventricle (online supplemental video 2). Our question is: is recombinant tissue plasminogen activator (rt-TPA) the appropriate treatment choice in order to dissolve this life-threatening clot?
Structured clinical question
In a very or extremely preterm newborn with intracardiac thrombosis not responsive to heparin treatment, is rt-TPA safe and effective (reduce or dissolve the clot), and if so what dose should be used?
We searched PubMed, EMBASE and Google Scholar for evidence relating to thrombolysis in preterm infants until 31 July 2021 using: (“preterm infant” OR “extremely low birth weight”) AND thrombosis AND (“recombinant tissue plasminogen activator” OR thrombolysis). The search yielded 86 articles after removing duplicates. All reference lists were also cross-checked, and four articles were added. No randomised controlled trial on this topic was available; therefore, case report, case series and retrospective studies were eligible for the review. Forty-two articles were fully evaluated, and 12 studies met the inclusion criteria (preterm infants below 32 weeks of GA affected by intracardiac thrombosis treated with rt-TPA). We further filtered each article by limiting cases of intracardiac thrombosis and the GA to less than 32 weeks. Twenty-eight preterm infants were finally involved in the analysis.
The use of central venous catheter in preterm infants is a major risk factor for right atrial thrombosis that may compromise cardiac function and/or cause pulmonary and systemic embolism.1 2 Therapeutic options include a ‘wait and watch’ conduct with ultrasonography follow-up, anticoagulant treatment with heparin or thrombolysis. Thrombectomy cannot be safely performed in preterm neonates because of its high invasiveness and the small calibre of vessels.3 International guidelines on the management of neonatal thrombosis are lacking and recommendations are necessarily based on extrapolation of principles of therapy from paediatric and adult guidelines, individual cases and common clinical practice.
With regard to anticoagulant therapy, unfractionated heparin is the most used drug in neonates. The recommended dose for preterm infants with GA <28 weeks is 25 IU/kg intravenously over 10 min, then 15 IU/kg/hour.4
Since the 1990s, LMWH, such as enoxaparin, has become the anticoagulant of choice in neonatal intensive care units5 because of its predictable and durable anticoagulant effect, the possibility for subcutaneous administration, which prevents repeated venous access in preterm babies, and its predictable pharmacokinetic properties.5 Recent evidence suggests a starting dose of 2 mg/kg/12 hours (equal to 150 IU/kg) in preterm infants.6 The goal of this treatment is to maintain an anti-factor Xa level of 0.5–1.0 IU/mL.7
Heparin-resistant thrombi or larger thrombi increasing risk or causing right outflow obstruction and pulmonary embolisation require a more aggressive and rapid treatment, such as thrombolysis to promptly facilitate clot dissolution. The International Society on Thrombosis and Haemostasis has included preterm birth <32 of GA among contraindications for rt-TPA thrombolysis.8 The American College of Chest Physicians guidelines9 suggest either anticoagulation or supportive care with ultrasound monitoring: however, if an untreated clot continues to increase in extension during echocardiographic follow-up, anticoagulant therapy should be started. When considering right atrial thrombosis in paediatric patients,10 features such as large size (>2 cm for term neonates: this threshold cannot be applied to preterm babies in whom the small size of right atrium in comparison with the clot size should be considered), pedunculated, mobile, or snake-shaped and mobile appearances were reported as high risk for disease progression, pulmonary embolism and death.
Thrombolysis therapy in neonates, especially in very and extremely preterm infants, is still limited because of the potential risk of severe bleeding and a lack of knowledge of the most appropriate dose of rt-TPA. Although actually there is no consensus about most appropriate dose of rt-TPA in preterm neonates, two rt-TPA dosing regimens have been suggested for children and term neonates11: high-dose rt-TPA (0.5–0.6 mg/kg/hour) given as a continuous infusion for 6 hours and eventually readministered after 24 hours, and a low-dose rt-TPA regimen administered as a starting dose of 0.03 mg/kg/hour that may be progressively increased to an hourly maximum dose of 2 mg/kg/hour and continued from 12 to 96 hours until clot dissolution. Even if the high-dose regimen could be more effective in life-threatening or limb-threatening clots, it is compounded by a major risk of bleeding and, therefore, it should be avoided in preterm infants.11 12
Reviewing the literature, 12 studies which reported 28 very or extremely preterm neonates who had pharmacological thrombolysis with rt-TPA for intracardiac thrombi were found13–24 (table 1). Their GA ranged from 23 to 31 weeks14 25 with a birth weight from 544 to 1300 g.13 21 The age at diagnosis of thrombosis was from 1 to 54 days of life.18 20 In all cases, sepsis, central venous, or arterial catheter or both were reported as concurrent risk factors.
Bolus dose of rt-TPA was administrated in nine cases with a dosage range of 0.05–1 mg/kg intravenously.14 15 18–21 24 We found that the following continuous infusion of rt-TPA was highly heterogeneous both in terms of dosage (range 0.01–1.2 mg/kg/hour)13 23 and duration (range 1–13 days).13–15 18 19 21 23 Low-dose rt-TPA was given to 16 of 28 neonates,13–18 20 22 24 while the remaining subjects received high-dose rt-TPA.13 14 18 19 21 23 Major complications occurred in four neonates (14%): three developed intraventricular haemorrhage (IVH), whose severity was not detailed, and one pulmonary haemorrhage.13 14 23 Three of these adverse events occurred in patients treated with high-dose rt-TPA.14 23 Complete resolution of clot was reported in 20 cases (71.4%),13–18 20–22 25 26 partial resolution in 4 (14%)13 14 16 23 and no resolution in 2 (7.1%).13 Eleven patients received prophylaxis with heparin after thrombolysis although the dosage and duration were heterogeneous.14 15 20 24 26
Therefore, before undertaking thrombolytic therapy, the bleeding and particularly IVH risks related to drug therapy must be carefully evaluated. Thus, it will be necessary to start a possible conservative therapy and possibly a heparin treatment reserving the thrombolytic therapy for otherwise unsolvable cases that expose the newborn to serious risks of embolism or mechanical obstruction linked to the thrombus itself.
In the case presented in the Scenario section, systemic thrombolysis was selected using low-dose rt-TPA infusion (started at 0.05 mg/kg/hour). Fresh frozen plasma (10 mL/kg) was given just before starting rt-TPA to optimise plasminogen level. Concurrent heparin infusion was reduced to 10 IU/kg/hours. Six hours later, echocardiography showed no improvement in clot size. Thus, rt-TPA dose was progressively increased to 0.1 mg/kg/hour. On subsequent echocardiography, the thrombus became smaller (online supplemental video 3), and after 8 hours it was no longer detectable thus rt-TPA was discontinued.
Clinical bottom line
Thrombolytic therapy with recombinant tissue plasminogen activator (rt-TPA) appears to be effective in lysing intracardiac clot in very and extremely preterm infants. (GRADE D)
Thrombolysis with rt-TPA should be reserved for cases unresponsive to conventional anticoagulant therapy after careful evaluation of the risks and benefits (life-threatening, pulmonary embolisation risk, etc). (GRADE D)
Due to the limited safety evidence available, it is recommended starting treatment with the lowest recommended dose (0.03 mg/kg/hour) and gradually increasing based on clinical response. (GRADE D)
Patient consent for publication
Contributors MC conducted the literature search, interpreted results and drafted the manuscript. IC conducted the literature search, interpreted results, contributed to the manuscript and edited through multiple revisions, and supervised the entire process. CD contributed to the manuscript and edited through multiple revisions. FM, ML, CC and SP were involved in the literature search and interpreting the results, and edited through multiple revisions.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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