ORIGINAL ARTICLE

The use of recombinant tissue plasminogen activator in themanagement of infective intracardiac thrombi in pre-term infantswith thrombocytopaeniajpc_1572 598..601

Ben Anderson,1 Prasanth Urs,2 David Tudehope2 and Cameron Ward1

1Department of Paediatric Cardiology, Mater Children’s Hospital and 2Division of Neonatology, Mater Mothers’ Hospital, Brisbane, Queensland, Australia

Abstract: Bacterial endocarditis complicated by the development of intra-cardiac thrombus presents a difficult management dilemma in thepre-term infant. Here we present our experience with three infants who had this condition, all of whom were successfully managed using therapywith recombinant tissue plasminogen activator (r-TPA). Therapy in one of the infants was particularly instructive, as the condition was furthercomplicated by severe thrombocytopaenia, making the decision to treat using r-TPA difficult.

Key words: bacterial endocarditis; neonate; thrombocytopaenia; thrombolysis.

The development of bacterial endocarditis and intracardiacthrombus is a rare but serious complication in the newborninfant. It can lead to life threatening complications of valvularobstruction or regurgitation with subsequent cardiac failure,pulmonary or systemic thrombo-embolism, rupture of venousstructures and superior or inferior venacaval syndrome. Thesepremature infants are often of very low birth weight, makingthe option of surgical treatment technically more difficult, andincreasing morbidity and mortality. This often leaves medicaltherapy as the sole treatment option for these children.

The preference of treatment between the thrombolytic agentsStreptokinase and Urokinase, and recombinant tissue plasmino-gen activator (r-TPA) varies between centres. Thrombolyticagents such as heparin and streptokinase are generally nolonger considered ideal in the neonatal period as they may leadto a systemic coagulopathy.1 r-TPA offers several theoreticaladvantages to newborn infants, including short half-life,minimal antigenicity, direct activation of plasminogen, lack ofinhibition by alpha-2-antiplasmin and localisation of fibrinolyticactivity.1–4 There have been several reports of successful use ofr-TPA in the management of intracardiac thrombus in newborn

infants,5–9 and in the paediatric age group where resolution ofthe vegetations with no complications were reported.10

In this case series we report on the successful use of r-TPA forthe management of intracardiac thrombus associated with sys-temic staphylococcus infection in three pre-term infants, one ofwhom was severely thrombocytopaenic.

Case Report 1

The first infant was a male, born at 26 weeks gestation byCaesarian section, weighing 800 g. He required nasal continu-ous positive airway pressure (CPAP) for the first 2 weeks of life,before extubation to room air. A central venous line wasinserted on day 9 of life for the provision of total parenteralnutrition. This line was removed on day 18. On day 20 of life,this infant developed severe apnoeic and bradycardic episodes,requiring ventilatory support. Late onset sepsis was suspected,and following septic screening antibiotics (vancomycin and gen-tamicin) were commenced. The blood culture subsequentlygrew Staphylococcus aureus. Seven days after commencing anti-biotics, on day 27 of life, this infant was noted to be tachycardicat 170–180 beats per minute, and a grade 3/6 systolic murmurwas heard. Echocardiography demonstrated a vegetation mea-suring 3 mm by 3 mm on the septal leaflet of the tricuspid valve.There was also a patent foramen ovale, with right to leftshunting.

At this time conservative management was continued, withflucloxacillin given in addition to the vancomycin. Repeatechocardiography 3 days later revealed that the vegetation hadincreased in size to 8 mm by 4 mm, and was highly mobile.Antibiotic treatment was continued, with repeat echocardio-graphy 3 days later showing no further change in vegetationsize (Fig. 1).

Based on these findings, therapy with r-TPA was commenced.r-TPA was infused at a dose of 0.2 mg/kg/h over 6 h for 5consecutive days. Each dose of r-TPA was preceded by an

Key Points

1 Neonates are at increased risk for the development of infectiveendocarditis.

2 Thrombolytic therapy may be a useful adjunct in the manage-ment of a difficult condition.

3 Thrombolytic therapy may be considered with caution in thecontext of thrombocytopaenia.

Correspondence: Professor David Tudehope, Director of Neonatology,Mater Misericordiae Mothers’ Hospital, Raymond Terrace, South Brisbane,QLD 4101, Australia. Fax: +61 7 3840 1949; email: david_tudehope@mater.org.au

Accepted for publication 16 March 2009.

doi:10.1111/j.1440-1754.2009.01572.x

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infusion of fresh frozen plasma at a dose of 10 mL/kg. Theresponse to this therapy was monitored with alternate dayechocardiography.

A reduction in size of the intracardiac thrombus was notedafter 3 days of therapy, with complete resolution after 8 daysfrom the initiation of therapy. Cranial ultrasound scan on day29 of life showed resolution of unilateral sub-ependymal hae-morrhage that had been noted on a day 7 scan. This infantproceeded to make a complete recovery, and repeat echocardio-graphy revealed normal cardiac function with an intact tricuspidvalve.

Case Report 2

A 34 week gestation male infant, with a birth weight of 2198 g,was delivered by Caesarian section, with Apgar scores of 7 at1 min and 9 at 5 min. The infant had respiratory distress atbirth, which required treatment with nasal CPAP, and a umbili-cal venous catheter (UVC) was inserted, remaining in situ for atotal of 6 days. On day 6 of life he developed recurrent apnoeicand bradycardic episodes, for which he underwent a septicscreen. Results of this screen provided further evidence of sepsis,revealing a toxic full blood count, elevated C reactive protein,and subsequent growth of Staphylococcus aureus on blood culture.Therapy was instituted with vancomycin and gentamicin,although the infant failed to respond to this treatment, and twosubsequent blood cultures grew the same organism. Based onthese results the antibiotics were changed to flucloxacillin andgentamicin.

Due to the failure of therapy to clear the blood cultures oforganisms the infant underwent echocardiographic evaluation.This demonstrated a vegetation measuring 8 mm by 5 mm atthe junction of the inferior vena cava and right atrium (Fig. 2).Antibiotic treatment was continued, and r-TPA was com-menced, given by intravenous infusion at a dose of 0.2 mg/kg/hover 6 h for five consecutive days. Prior to each dose the infantreceived fresh frozen plasma at a dose of 10 ml/kg.

The response to therapy was monitored with alternate dayechocardiography. A reduction in the size of the vegetation wasshown after 6 days, with complete resolution 13 days after the

initiation of therapy with r-TPA. He recovered completely fromthe sepsis, and subsequent echocardiography demonstratedresolution of the thrombus with an otherwise normal heart.

Case Report 3

A 36-week gestation female infant, who was small for gesta-tional age, weighing 1669 g at delivery, had Apgar scores of 8at 1 min and 9 at 5 min. Early onset respiratory distress neces-sitated the use of nasal continuous positive airway pressureventilation for one day only. Hypoglycaemia secondary tohyperinsulinism required treatment with intravenous glucose,and a UVC was inserted on day 1 of life. The position of thecatheter tip was confirmed on x-ray to lie in the ductusvenosus. The UVC was changed for a peripheral IV line on day5 of life.

On day 7 of life the infant developed signs of sepsis, with atoxic full blood count, and a platelet count of 9. She was com-menced initially on amoxicillin and gentamicin, before theamoxicillin was changed to vancomycin when blood culturescollected at the onset of this episode grew Staphylococcus aureus.

A 2/6 pan systolic murmur at the left sternal edge was aus-cultated for the first time on day 9 of life. Echocardiographyrevealed a 7 mm by 5 mm vegetation on the right atrial aspectof the septal leaflet of the tricuspid valve, with associated mildto moderate tricuspid regurgitation. Cephalothin was added tothe antibiotic regime given these findings.

On day 14, the vegetation had increased to 10 mm by 6 mm,and the tricuspid regurgitation persisted, with a peak pressuregradient of 35 mmHg (Fig. 3). The platelet count at this timeremained problematic, despite platelet transfusions over theprevious days. Immediately following transfusion with 2 unitsof platelets, the count rose to 158, however, 12 h later this hadfallen again to 37. It was postulated that the thrombocytopaeniamay have been secondary to platelet consumption by the int-racardiac vegetation that had continued to increase in size.

The decision to commence treatment with r-TPA was basedon the increase in size of the intracardiac vegetation, presumedconsumptive thrombocytopaenia, and the high likelihood of

Fig. 1 Apical four chamber view showing thrombus formation on septal

leaflet of tricuspid valve.Fig. 2 Sub-xyphoid view showing thrombus formation at the junction of

inferior vena cava and right atrium.

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mortality with a surgical procedure to remove the lesion. This,however, presented a dilemma with regard to the risk of coagu-lopathy. In consultation with the haematologist a protocol wasdevised:

Two units of platelets were given over 4 h, accompanied by2 mg of frusemide and then 10 mL/kg of fresh frozen plasmaover 1 h. Then r-TPA was given at 0.2 mg/kg/h for 6 h. Threehours into the infusion of r-TPA the fibrinogen levels werechecked. The full blood count was checked at the end of theinfusion, and if less than 50 then one unit of platelets was to begiven. This procedure was repeated on day 2, beginning 19 hafter the r-TPA dose, so that the second dose of r-TPA began 23 hafter the first.

Twenty-four hours after the first dose of r-TPA the vegetationhad not changed in size, but subjectively appeared less dense ontwo-dimensional echocardiography. By 96 h it had decreased insize, measuring 2 mm by 3 mm on the septal leaflet of thetricuspid valve. There was moderate tricuspid regurgitation,which appeared to be through the valve leaflet itself, accompa-nied by apparent prolapse of the septal leaflet of the valve. r-TPAtreatment was repeated for the third dose 5 days after the firstdose. At day 11 post r-TPA treatment, the vegetation sizeremained stable at 2 mm by 4 mm, with continuing valveregurgitation.

At this stage no further r-TPA treatment was given, due to thestatic size of the vegetation following the third dose of r-TPA.The baby continued on a prolonged course of flucloxacillin.

Discussion

The pre-term infant with infective endocarditis (IE) andintracardiac thrombus presents an interesting managementdilemma. Although spontaneous regression of intracardiacthrombi is theoretically possible, early treatment is advised dueto the inherent risk of thrombo-embolism. The potential com-plications of IE and intracardiac thrombus in the neonate relatepredominantly to either destruction of local structures or embo-lism of the vegetation to a distal site. Right atrial thrombi mayenlarge, leading to obstruction of the tricuspid valve orifice, or

superior/inferior venacaval syndrome. Macro or micro emboli-sation in the systemic or pulmonary circulations may occur.Previous authors have distinguished risk factors on echocardio-graphy for complications. These have included vegetation size>10 mm, size increasing during therapy and worsening of val-vular or ventricular function.11

Pre-term infants are predisposed to thrombotic disordersbecause of their inherent deficiency in homeostasis and relianceon central venous lines for monitoring, delivery of drugs andtotal parenteral nutrition.12,13 Other factors predisposing toincreased thrombin generation with subsequent fibrin deposi-tion or thrombus formation are peripartum asphyxia, septicae-mia and surgery. The incidence of neonatal thrombosis hasbeen estimated at 5.1 per 100 000 live births, or 2.4 per 1000newborns admitted to a neonatal intensive care unit.2 Inthese studies, 89% of thrombus formation was catheter related,of which 29% was associated with or complicated by systemicinfection.

Pre-term infants are at risk of IE for a number of reasons. Ofthe paediatric cases of IE, 8–10% occurs in children withoutstructural heart disease or other identifiable risk factors.11 Thefrequency of neonatal IE of 4.3 per 100 cases has been estimatedin one series.14 These infections are usually secondary to Staphy-lococcus aureus. Indwelling catheters have the potential to trau-matise the endocardium and valvular endothelium, exposingthe underlying sub-endothelial collagen. These sites are thenthrombogenic, facilitating deposition of platelet clumps, fibrinand red blood cells.11 Thrombus formation occurs because ofthe combination of high pro-thrombotic activity, low levels ofnatural anticoagulants and imbalances in the fibrinolytic sys-tems.2 These lesions are then at risk of becoming colonised bytransiently circulating bacteria. These infections often occur onthe right side of the neonatal heart, corresponding to the cath-eter position.

Surgical treatment options consist of surgical resection of thevegetation from the heart, with repair of any associated struc-tural damage. These procedures are often technically difficultor impossible in premature, low birth weight infants and insome cases these factors preclude surgical intervention. Surgicalmortality alone reaches significantly high rates. Nomura et al.reported thirty cases of bacterial endocarditis requiring surgicalintervention, with an overall mortality of 24.5%. While therewere 10 neonates in this series it was not specified how many ofthese were operated on or their outcomes. As surgical manage-ment for intracardiac thrombi in neonates is associated withhigh mortality3 medical management is preferred, and may bethe only feasible modality of treatment. The choice of treatmentlies between Streptokinase, Urokinase and r-TPA, in addition toappropriate antibiotic therapy. Thrombolytic agents offer thetheoretical possibility of reducing vegetation size and enhancingantibiotic diffusion by promoting fibrin degradation.

The third case highlighted the management dilemma thatoccurs in the context of thrombocytopaenia and intra-cardiac,or indeed any major, thrombi. The decision to use r-TPA in thiscontext increases the risk of haemorrhage, which must beweighed against the risk of the intracardiac thrombus and itspossible complications. It is likely that the rapidly enlargingthrombus itself contributes to the thrombocytopaenia throughplatelet consumption within the lesion.

Fig. 3 Apical four chamber view showing vegetation on septal leaflet of

tricuspid valve.

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r-TPA activates plasminogen, which lyses fibrin and fibrino-gen, producing fibrinogen degradation products that inhibitthrombin, which then leads to clot resorption and prevention offurther clot deposition. While the effects of r-TPA tend to bemore localised than other agents, the potential for causing sig-nificant haemorrhage still exists. For this reason the therapy inneonates is combined with the provision of fresh frozen plasma,and in the case of thrombocytopaenia, platelet therapy.

Close monitoring of the coagulant status was employed withthe use of r-TPA. Three hours into the infusion fibrinogen levelswere checked. If the levels were below 1, the infusion wasceased to allow the fibrinogen to recover. The platelet countwas also monitored, and if the count fell below 50, the infantwas treated empirically with platelet therapy. This procedurewas repeated for each infusion with r-TPA, and no complica-tions were seen in these cases.

In septic pre-term infants, a high index of suspicion is neces-sary to diagnose infective endocarditis and intracardiac vegeta-tions, which can be very difficult to diagnose clinically, due tothe non-specific symptoms and signs that can be attributedto a range of other conditions. In our centre all infants withdocumented staphylococcal or fungal septicaemia undergo 2Dechocardiography to look for evidence of cardiac involvement,due to the relatively high rates of cardiac involvement in theseinfants.

The success with use of r-TPA in our patients and severalother reports suggest that r-TPA can be considered for manage-ment of infants with intracardiac vegetations related to centralvenous catheterisation and/ or systemic bacterial infection, andshould be seriously considered even in the presence of con-sumptive thrombocytopaenia. The apparent effectiveness ofr-TPA in treating intracardiac vegetations in neonates raises theissue of management of this condition in older children. Furtherstudy is required to delineate whether r-TPA can be used as afirst line therapy in older children.

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