Pulmonary artery thrombus is a rarely reported complication in premature neonates. The management of life-threatening thrombotic events in neonates is controversial, especially regarding the use of thrombolytics versus anticoagulation alone for treatment. We report a case of a premature neonate with symptomatic pulmonary artery thrombus treated with recombinant tissue plasminogen activator who survived without bleeding complications.
Pulmonary artery thrombosis is a rare and likely underreported complication in children1 as well as in neonates in the neonatal intensive care unit. Reports indicate that identification of pulmonary thrombus is challenging for physicians, as clinical signs can mimic other morbidities in critically ill neonates, such as persistent pulmonary hypertension of the newborn2 and congenital heart disease3 as well as mild pulmonary changes such as those noted with pulmonary edema. Risk factors for pulmonary artery thrombosis in neonates include maternal chorioamnionitis, maternal diabetes mellitus, neonatal sepsis and the presence of indwelling central catheters.4 No consensus exists regarding the proper pharmacologic treatment in neonates with pulmonary thromboses. We present the case of a 3-week-old extremely low birth weight neonate with acute onset of significant respiratory distress, who was diagnosed with symptomatic pulmonary artery thrombus, and who was treated with tissue plasminogen activator (tPA) and survived without major bleeding complications.
The patient was a 660 g African-American male born at 26 weeks' gestation via urgent caesarian section for preterm labor and breech presentation. The mother was a 33-year-old gravida 4 para 2 woman. Her pregnancy was complicated by chronic hypertension, treated with labetalol, type 2 diabetes mellitus, treated with glyburide and fetal growth restriction with reversal of end diastolic flow in the umbilical artery on fetal ultrasound 2 days prior to delivery. She received four doses of antenatal betamethasone. The infant was intubated in the delivery room, given surfactant and brought to the neonatal intensive care unit for routine extremely low birth weight infant care.
The subsequent 3-week postnatal course was unremarkable. He was extubated and transitioned to continuous positive airway pressure on postnatal day 6 and eventually to high-flow nasal cannula by postnatal day 11. He advanced to enteral feedings of donor breast milk to a total volume of 100 ml kg−1per day via nasogastric tube without difficulty. The remainder of caloric needs was provided by parenteral nutrition. Vascular access was through an umbilical venous catheter, which was removed on postnatal day 6 and replaced with a peripherally inserted central catheter in the left lower extremity. Per unit protocol, heparinized fluids (0.5 units ml−1) were utilized in both catheters. In the first postnatal week, routine head ultrasound showed no evidence of intraventricular hemorrhage and an echocardiogram obtained for evaluation of heart murmur on postnatal day 9 was interpreted as a closed ductus arteriosus and left-sided physiologic branch pulmonary artery stenosis.
On postnatal day 20, (corrected age 29 weeks and weight 750 g), the infant’s clinical condition worsened acutely. He required escalation of respiratory support to continuous positive airway pressure with increasing oxygen requirements. The treatment team noted a new systolic murmur near the upper sternal border. He began to have more frequent episodes of apnea, bradycardia and desaturation requiring nursing intervention. He underwent a sepsis evaluation, empiric antibiotics were begun and he was transfused (10 ml kg−1) with packed red blood cells secondary to potentially symptomatic anemia (hematocrit, 26%). Despite these interventions, the patient’s cardiorespiratory status worsened, and he was intubated and placed on a ventilator on postnatal day 21. A chest radiograph at that time suggested decreased appearance of the pulmonary vasculature on the left compared with the right (Figure 1). An echocardiogram was repeated and showed an echolucency in the proximal left pulmonary artery consistent with thrombus causing near complete or complete occlusion of the left pulmonary artery (Figure 2a) (see Supplementary Video 1). The infant remained critically ill with long periods of apnea while on the ventilator and a continued increased oxygen requirement with intermittent episodes of desaturation.
Discussion began regarding possible anticoagulation versus thrombolytic therapy. A computed tomography angiography scan of the chest was performed to better delineate the anatomy of the left pulmonary artery given the interpretation of branch pulmonary artery stenosis on initial echocardiogram. The computed tomography angiography scan showed normal main and right pulmonary arteries, but confirmed a markedly diminished caliber of the left pulmonary artery immediately after its takeoff from the main pulmonary artery with a filling defect within the left pulmonary artery and diminished pulmonary arterial blood flow to the left upper lobe. As with the previous chest radiograph, it suggested asymmetric pulmonary blood flow to the lungs with the right thorax receiving a disproportionately greater degree of pulmonary arterial blood supply.
Given that the infant was symptomatic from the thrombus, the decision was made to begin thrombolytic therapy with tPA. Hematologic parameters immediately prior to treatment were normal including a prothrombin time of 13.3 s (INR 1.1), partial thromboplastin time of 27.6 s and fibrinogen of 299 mg dl−1. The hematocrit was stable at 37% and platelets were normal at 383 × 103 mm−3. The infant received a bolus dose of 0.5 mg kg−1 over 1 h followed by a continuous infusion of 0.25 mg kg−1 per hour through a dedicated peripheral line. The evolution of the thrombus was followed with serial echocardiograms, which revealed resolution of the thrombus and return of blood flow through the left pulmonary artery on postnatal day 23 after 40 h of therapy (Figure 2b). The caliber of the left pulmonary artery remained slightly smaller compared with the right. No bleeding complications of therapy were observed. A head ultrasound immediately after therapy showed no intraventricular hemorrhage. Post-thrombolytic hematologic values remained within normal parameters.
Once tPA was discontinued, the patient was begun on low-molecular-weight heparin, enoxaparin. The starting dose was 1.8 mg kg−1 dosed via the subcutaneous route every 12 h with a target anti-Xa level of 0.6 to 1 units ml−1. The Pediatric Hematology Service was consulted for surveillance and maintenance therapy. He was extubated to continuous positive airway pressure 5 days after initiation of thrombolytic therapy and eventually weaned to room air without difficulty. He advanced on enteral feedings and transitioned to convalescent care without additional complications. Due to the risk of bleeding and the lack of clear guidelines for long-term anticoagulation in premature infants, enoxaparin was discontinued after 6 weeks of therapy once the absence of residual clot was confirmed with echocardiogram. A workup for hypercoagulable states including fibrinogen levels, protein C and S, antithrombin III, anticardiolipin antibody, lipoprotein a, anti-beta 2 glycoprotein antibody, homocysteinemia, factor V Leiden and lupus anticoagulant was negative. Head ultrasound 1 week prior to discharge, 10 weeks after the event, was normal. A final echo on the day prior to discharge showed no residual thrombus (Figure 2c) (see Supplementary Video 2). He was discharged to home at 40 weeks corrected gestational age at a weight of 2230 grams with no respiratory support, full enteral feeds orally, and chlorothiazide.
The infant highlighted in this case demonstrated several risk factors for the development of pulmonary artery thrombosis, including maternal diabetes mellitus, the presence of two indwelling central venous catheters and possible neonatal sepsis following preterm labor. Pulmonary artery thromboses have been commonly associated with the presence of umbilical catheters.4 The umbilical venous catheter had been removed by postnatal day 6. At the time the pulmonary thrombus was discovered, the only vascular access was through a lower extremity peripherally inserted central catheter that was confirmed to terminate in the inferior vena cava. The lowest rate of heparinized fluids running through this peripherally inserted central catheter was 4.4 ml per hour, much higher than a minimal carrier rate. Umbilical artery catheters have been shown to be at lower risk of embolism in the first few postnatal days,5 so extended use is generally avoided in the otherwise well infant. In our case, an arterial catheter was never utilized. The patient also had a minor anatomic abnormality in the form of peripheral pulmonic stenosis, and it is likely that this anatomic narrowing further contributed to the formation of the thrombus. After diagnosis, retrospective review of the first echocardiogram (postnatal day 9, 2 weeks prior to diagnosis), which was performed to evaluate for patient ductus arteriosus, was still interpreted as branch pulmonary artery stenosis alone without evidence of thrombus.
The acute management of symptomatic pulmonary thrombosis remains controversial and often leads to risk/benefit assessments on a patient-by-patient basis.6 Neonatologists and pediatric hematologists have relied on a few specific sources for clinical guidelines for the treatment of acute thromboembolism in children. The 1-800-NOCLOTS telephone consultation service, begun by Dr. Maureen Andrew in 1994, remains the most used consultation service in North America for neonates and children who have thrombotic problems.7 The second resource is the American College of Chest Physicians (ACCP) Guidelines for Antithrombotic Therapy in Neonates and Children.8 Our tPA dosing protocol was created after review of several small case series showing effectiveness of a loading dose9,10 and an additional retrospective study of catheter-related thrombosis in neonates demonstrating efficacy of a loading dose followed by a continuous infusion for 1 to 4 days.11 The duration of therapy in our case was guided by serial echocardiograms to assess resolution of the thrombus.
The use of thrombolytics in premature neonates has historically been avoided due to concerns of intraventricular hemorrhage6 and other bleeding complications. They therefore have been reserved for infants with life-threatening thrombosis or infants with multiorgan dysfunction due to the high mortality risk in these patients. Our patient survived therapy without major bleeding complications or intraventricular hemorrhage. The subsequent use of enoxaparin in neonates is supported by the ACCP evidence-based clinical guidelines previously mentioned.8 In our case, enoxaparin was discontinued after 6 weeks of therapy, which is at the lower end of recommended duration of therapy due to continued evidence of resolution of the thrombus. No randomized trials of thrombolytic therapy versus anticoagulation alone have been undertaken in neonates.12
We present the case of a premature, extremely low birth weight neonate with a symptomatic pulmonary thrombotic phenomenon successfully treated with tPA, followed by anticoagulation with enoxaparin. There were no bleeding complications. Further comparison studies of anticoagulation versus thrombolytic therapy alone or in combination with anticoagulation therapy in neonates for the management of symptomatic thromboembolism are needed, as no randomized clinical trials exist.
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We thank Dr Christoph Hornik and Dr Piers C Barker for providing echocardiogram images and videos.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Journal of Perinatology website
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DeMeo, S., Sherwood, A., Hornik, C. et al. Pulmonary artery thrombus in a premature neonate treated with recombinant tissue plasminogen activator. J Perinatol 34, 569–571 (2014). https://doi.org/10.1038/jp.2014.34
- pulmonary arterial thrombus
- recombinant tissue plasminogen activator
A Previously Healthy Premature Infant Treated With Thrombolytic Therapy for Life-threatening Pulmonary Artery Thrombosis
Journal of Pediatric Hematology/Oncology (2016)