Nonbacterial endocardial thrombosis in neonates: Relationship to persistent fetal circulation

January I982 The Journal o f P E D 1 A T R I C S

117

Nonbacterial endocardial thrombosis in neonates: Relationship to persistent fetal circulation Thirteen neonates with nonbacterial endocardial thrombosis are described These infants demonstrated a distinctive coagulopathy characterizedprimarily by thrombocytopenia and widespread thromboembolism. There was also a statistically significant association of N B E T with persistent fetal circulation. We postulate a relationship between hypoxia, disturbed hemodynamics, and activation of vasoactive and platelet proaggregatory substances as a pathogenetic mechanism for the observed association of PFC, thrombo~Ttopenia, and N B E T

W. Robert Morrow, M.D.,* Joel E. Haas, M.D., and Denis R. Benjamin, M.B., B.Ch., S e a t t l e , W a s h .

NEONATAL NONBACTERIAL ENDOCARDIAL T H R O M B O SI S characteristically affects infants of more than 34 weeks' gestational age and has been associated with a coagulopathy, disseminated thrombosis, as well as intracardiac placement of Umbilical venous catheters. 1~ However, the clinical and pathologic features of infants with NBET have not been extensively characterized. We describe 13 neonates with nonbacteriaI endocardial thrombosis. A distinctive c0agulopathy and an unusually high prevalence of persistent fetal circulation appear to be characteristic of this syndrome. METHODS Thirteen infants with neonatal NBET were identified from reports of postmortem examinations between January, 1974, and July, 1980. None of these infants had structural heart disease or congenital anomalies. Infants who were autopsied over the same period and who were 34 weeks, gestational age or greater but had no evidence of NBET, congenital anomalies, or structural heart disease were used as controls. Clinical data were obtained by retrospective chart review on cases and controls. Laboratory evaluations, From the Department of Pediatrics, University of Washington, The Children's Orthopedic Hospital and Medical Center, and Department of Laboratories, The Children's Orthopedic Hospital and Medical Center. *Reprint address: Children's Orthopedic Hospital, P.O. Box 5371, Seattle, WA 98105.

0022-3476/82/010117+06500.60/0 9 1982 The C. V. Mosby Co.

echocardiograms, electrocardiograms, and cardiac catheterizations had been performed for clinical indications. Blood was usually obtained from umbilical artery catheters and studies performed by standard methods. Values for coagulation tests greater than stated upper limits were considered normal if accompanied by a proportionate increase in controls. Abbreviations used NBET: nonbacterial endocardial thrombosis PFC: persistent fetal circulation PT: prothrombin time PTT: partial thromboplastin time TT: thrombin time DIC: disseminated intravascular coagulation PDA: patent ductus arteriosus IRDS: idiopathic respiratory distress syndrome

For purposes of this study persistent fetal circulation was considered "documented" in severely hypoxemic infants with one or more of the following: (1) Right-to-left shunt (right radial to umbilical artery Pa% gradient > 20 m m Hg). (2) Echocardiographic evidence of elevated pulmonary artery pressure or resistance. (3) Cardiac catheterization data indicating increased pulmonary vascular resistance, increased pulmonary vascular pressure (greater than systemic), and a right-to-left shunt (atrial or ductal). Complete autopsies were performed on 13 cases and 28 controls. In complete autopsies tissue from all major

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The Journal of Pediatrics January 1982

Fig. 1. Gross appearance of a tricuspid lesion occurring on the atrial surface Of the valve. RA = Right atrium; RV = right ventricle. Table I. S u m m a r y of clinical findings in cases a n d controls

Number Mean gestational age (wk) Mean weight (gm) Mean age at death (days) Sex ratio (M/F) Clinical IRDS Sepsis/pneumonia Asphyxia Meconium aspiration Persistent fetal circulation Catheters Umbilical artery Umbilical vein Other*

NBET

Control

13 37.5 (SD = 3.5) 2,947 (SD = 623) 6.25 1.6/1.0

29 37.6 (SD = 2.7) 2,813 (SD = 595) 3.9 1.5/1.0

9 1 5 2 7 13 3 0

24 11 4

*"Other" catheters were percutaneous central venous lines inserted at various sites_ organ systems Was fixed in 10% buffered formalin a n d e m b e d d e d in paraffin. Six m i c r o n sections were stained with h e m a t o x y l i n a n d eosin for light microscopic examination. W h e n e n d o c a r d i a l t h r o m b o s e s were observed on gross inspection of the heart, sections of involved cardiac tissue were o b t a i n e d a n d p r e p a r e d as above. G r a m stains of endocardial t h r o m b o s e s were p e r f o r m e d in nine o f 13 cases. Analysis of data for statistical significance was performed using the Yates corrected chi square and the Student t test.

RESULTS Clinical findings. Cases and controls were similar in m e a n gestational age, weight a n d sex ratio (Table I). All N B E T cases h a d severe respiratory disease. T h e r e was a statistically significant ( P ~ 0.02) association o f P F C a n d NBET. I R D S was more c o m m o n l y observed i n cases (P _< 0.05) whereas sepsis occurred more often in controls. Seven of 13 N B E T cases h a d d o c u m e n t e d P F C c o m p a r e d to four o f 29 controls (P < 0.02). In infants with NBET, three h a d a right radial to umbilical artery gradient, two h a d cardiac catheterization proven PFC,

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Fig. 2. Microscopic appearance ofendocardial vegetations. The mass is adherent to the valve leaflet where endothelium is denuded. Typically, few cellular elements are seen in these homogeneous eosinophilic masses. Table II. Abnormal coagulation data in cases and controls*t

Platelet (1,O00/ml) NBET (n = 7) Mean Range SD Controls (n = 8) Mean Range SD

I

PT

] ]

PTT (sec)

TT

Fibrinogen (mg/d o

26 7-42 13

17 14-27 4

75 46-152 36

33 16-80 22

138 26-252 79

104 35-268 90

86 20-300 105

149 39-300 91

93 12-300 102

55 0 200 68

*Abnormalities were observed prior to the administration of tolazoline or blood products. tNormal values: Platelet counts ~ 100,000/ml, PT "< 15, PTT <_ 80, TT < 31, fibrinogen >_ I00 mg/dL

and three had echocardiographic evidence of pulmonary hypertension. Echocardiographic findings included prolonged right ventricular systolic ejection intervals, right ventricular dilatation, abnormal pulmonic value motion, tricuspid regurgitation, demonstration of fight-to-left shunt, or a combination of the above? In some infants PFC was diagnosed by more than one method. A m o n g the remaining neonates with NBET, six had clinical courses indistinguishable from PFC but lacked documentation. Only two additional controls, had clinical courses consistent with PFC. Eight complete coagulation profiles (platelet count, PT, PTT, TT, fibrinogen) were performed in seven N B E T cases, and nine complete profiles were performed in eight

controls. One profile was completely normal in each group (Table II). Patients with N B E T had marked thrombocytopenia. Some neonates with N B E T had mild elevations of PT, PTT, TT, or mild hypofibrinogenemia. Controls with abnormal coagulation profiles had greater variation in all values than did patients with NBET; hypofibrinogenemia and elevations of PT, PTT, and TT were pronounced in these infants. Control subjects with thrombocytopenia had other abnormalities of the coagulation profile, particularly hypofibrinogenemia. Pathologic findings. The principal pathologic finding among cases was the presence of nonbacterial endocardial thromboses (Fig. 1). These vegetations were tan, friable, and attached either to the atrial surface of atrioventricular

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Fig. 3. A platelet thrombus is seen in a pulmonary arteriole accompanying a terminal bronchiole. Atelectasis and hyaline membranes are present as well.

Table III. Distribution of neonatal endocardial thrombosis in reported series*

Atrioventricular valves Tricuspid Mitral Atrial Left Right Ventricular Left Right

Present

Favara et al 1

Symchych et aP

13 5

16 14

2 2

0 5

0 1

3 6

0 0

0 0

1 0

*Numbers represent number of endocardial thromboses. Some infants had thrombosis at more than one site. valves or to the atrial endocardium; tricuspid vegetations predominated, with mitral lesions and right atrial lesions occurring less frequently (Table IIl). One heart had involvement of all three sites. Right atrial thromboses were often located on the right atrial septum near the foramen ovale. Microscopically, endocardial thrombi were homogenous eosinophilic masses adherent to the cardiac surface where endothelium was denuded (Fig. 2). Few cellulai" elements were visible in these platelet masses. However, sparsely distributed degenerating leukocytes and erythrocytes were seen. Gram stains of sections from nine cases exhibited no organisms. Extracardiac thromboembolism was observed in infants

with N B E T and in controls but with a different pattern of distribution (Table IV). Most patients with N B E T had microscopic pulmonary thromboemboli (10/13); this was an u n c o m m o n finding in controls (5/29). Thrombosis was more likely to be systemic in controls and was interpreted as a reflection of DIC. Typically, pulmonary thromboemboli were identical in appearance to the accompanying endocardial lesions (Fig. 3). Many infants with N B E T had extensive arterial lesions varying from large branches of lobar pulmonary arteries to precapillary intra-acinar arterioles. One case had segmental infarction related to the presence of such a large vessel thrombus. Most, however, occurred at or distal to arterial branches supplying single acini. The distribution of systemic thromboemboli was similar in the two groups (Table IV). However, in two N B E T cases coronary artery thromboemboli were demonstrated; this was not observed in controls (Fig. 4). Thrombi contiguous with or attributable to umbilical artery catheters were not included in the data. DISCUSSION Nonbacterial endocardial thrombosis (nonbacterial thrombotic endocarditis) is well described in adults? However, this syndrome has been rarely observed in neonates. Sporadic reports appeared as early as 1935 ~ but two recent reports have revived interest in this entity.1. Various events have been cited as possible etiologic

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Fig. 4. A coronary artery thrombosis in a patient with histologically similar mitral vegetations. factors, including polycythemia, intracardiac placement of umbilical venous catheters, disseminated intravascular coagulation, and hypoxia. 1. . . . . 7 All infants reported have been "mortally ill ''1 and many had some evidence of thrombocytopenia or coagulopathy. In most series, including our own, infants have been at least 34 weeks' gestation or older. In contrast, ten neonates reported by Symchych et al ~ ranged from 24 to 40 weeks' gestation (seven of ten less than 1,500 gm). Eight infants in that study had intracardiac central venous lines. In our series there was no association between N B E T and intracardiac placement of umbilical venous catheters. In adults N B E T is clinically and pathologically associated with DIC. ~ In neonates thrombocytopenia with or without an accompanying coagulopathy was observed by Favara et al. 1 They postulated the existence of a platelet thrombotic process in the pathogenesis of N B E T differing from DIC. In our series thrombocytopenia was the predominant and often the only manifestation of coagulopathy in N B E T cases. This was in contrast to controls, in w h o m hypofibrinogenemia and elevations of PT, PTT, and TT were pronounced. In controls thrombocytopenia was only observed in association with a more generalized coagulopathy. The distribution of endocardial vegetations in our patients was similar to that observed by other investigators .... ~. 7 (Table III). The prevalence of lesions on the tricuspid valve and the distinct absence of lesions on semilunar valves is in agreement with data reported by

Table IV. Postmortem distribution of extracardiac thrombosis in N B E T cases and controls

Extracardiac site Pulmonary alone Pulmonary and systemic Systemic alone None Sites of systemic thrombosis Hepatic Arterial Venous (hepatic) Renal Splenic Adrenal Intracranial Coronary Gastrointestinal

NBET

Control

5 6 1 1

2 3 7 17

4 2 2 2 1 1 1 2 0

3 1 2 2 1 2 0 0 2

Favara et al? However, Symchych et al ~ reported a greater prevalence of lesions at various locations within the right atrium, left atrium, and left ventricle. This discrepancy may be related to the presence ofintracardiac catheters in a large n u m b e r of their patients. In contrast to their report, we observed no left atrial or ieft ventricular lesions. Adults characteristically have vegetations of the mitraI, aortic, and tricuspid valves, in that order? Lesions of semilunar valves have not been reported in neonates. In patients with NBET, extracardiac thromboembolism

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most often involved the pulmonary circulation. W h e n systemic thrombi were present they appeared to be related to the presence of lesions on the mitral valve or the foramen ovale. No distinction could be made between thrombosis and thromboembolism. The occurrence of thrombi in pulmonary veins (one case) and hepatic veins (two cases) suggests that disseminated thrombosis without embolization may occur. The one diagnosis that was clearly more prevalent in N B E T cases in our series was persistent fetal circulation (P <_ 0.02). This diagnosis has not been previously associated with NBET, although some case reports are compatible with that diagnosis.7 An association of thrombocytopenia with PFC has been reported by Segall et al? The association of nonbacterial endocardial thrombosis, thrombocytopenia, and persistent fetal circulation suggests a number of pathogenetic mechanisms. One possibility is the release of vasoactive, platelet proaggregatory substances into the circulation as a result of hypoxia a n d / o r endothelial injury. Thromboxane A~ has been shown to have strong platelet proaggregatory effects/" 11 and is also a mediator of pulmonary vasoconstriction, which could raise pulmonary vascular resistance and produce the syndrome of persistent fetal circulation. Other mediators of pulmonary vasoconstriction include PGF2A ~, 11 and serotonin. Circulating thromboxane As, PGF~A, serotonin, or other substances may originate at the site of endocardial or endothelial injury, or may be elaborated during .platelet aggregation and thrombosis. The relationships among prostaglandins, serotonin, and thromboxanes and the pulmonary circulation as well as platelet aggregation have been recently reviewedY -11 Regardless of what the initiating event may be, it seems likely that the release of mediators of pulmonary vasoconstriction by the aggregating platelets on the endocardium and in the pulmonary arterial circulation may contribute to the persistence of high pulmonary arterial pressures. Alternatively, altered hemodynamics in PFC may contribute to the occurrence o f endocardial thrombosis. Lesions were most frequent on the tricuspid valves, followed by the right atrial surface and mitral valves. In

The Journal of Pediatrics January 1982

the presence of a right-toqeft atrial shunt (in PFC), this pattern of thrombosis would correspond to the direction of blood flow and a gradient of decreasing hypoxemia. Turbulence and hypoxemia produced in this way could account for the unique distribution of endocardial lesions in neonates. In summary, we suggest that disturbed hemodynamics and activation of vasoactive platelet proaggregatory substances account for the observed association of PFC, thrombocytopenia, and neonatal nonbacterial endocardial thrombosis. We appreciate critical review of this report by Gregory J. Redding, M.D., and Christopher B. Wilson, M.D. We are also indebted to Mrs. Paula Livesley for secretarial assistance in preparing this manuscript. REFERENCES

1. Favara BE, Franciosi RA, and Butterfield LJ: Disseminated intravascular and cardiac thrombosis of the neonate, Am J Dis Child 127:197, 1974. 2. Symchych PS, Krauss AN, and Winchester P: Endocarditis following intracardiac placement of umbilical venous catheters in neonates, J PEDIATR90:287, 1977. 3. Johnson GL, Cunningham MD, Desoli NS, Cottrill CM, and Noonan JA: Echocardiography in hypoxemic neonatal pulmonary disease, J PEDIATR96:716, 1980. 4. Kim H, Suzuki M, Lie JT, and Titus JL: Nonbacteria thrombotic endocarditis (NBTE) and disseminated intravascular coagulation (D1C), Arch Pathol Lab Med 101:65, 1977. 5. Plant A, and Sharnoff G: Acute valvular endocarditis in the newborn, Arch Pathol 20:582, 1935. 6. McGuiness GA, Schieken RM, and Maguire GF: Endocarditis in the newborn, Am J Dis Child 134:577, 1980. 7. Krous HF: Neonatal nonbacterial thrombotic endocarditis, Arch Pathol Lab Med 103:76, 1979. 8. Segall ML, Goeztman BW, and Schick JB: Thrombocytopenia and pulmonary hypertension in the perinatal aspiration syndromes, J PEDIATR96:727, 1980. 9. Olley PM, and Coceani F: The prostaglandins, Am J Dis Child 134:688, 1980. 10. Longnecker GL: Review of platelet prostanoid biochemistry and pharmacology, Ala J Med Sci 17:270, 1980. 11. Cassin S: Role of prostaglandins and thromboxanes in the control of pulmonary circulation in the fetus and newborn, Semin Perinatol 4:101, 1980.