Neonatal aseptic cardiac valvular thrombosis--an evolving syndromereport of case

              Neonatal aseptic cardiac valvular thrombosis
An evolving syndrome: Report of case
RONALD V. MARINO, DD., MPH
Camden, New Jersey
DARRYL A. ROBBINS, DD., FAAP
Columbus, Ohio
A case is presented of a neonate in
whom aseptic thrombotic vegetations
on tricuspid and mitral valves were
found at autopsy. Cases previously
reported in the literature are
compared and contrasted in order to
focus attention on antenatal,
perinatal, and postnatal risk factors.
Aseptic cardiac valvular thrombosis
is suggested as a descriptive name for
this condition.
Verrucous lesions on normal neonatal heart
valves have been infrequently reported at post-mortem
examination. With the emergence of
neonatology as a subspecialty, recognition of and
interest in this phenomenon has increased.
The evolution of a unified concept of neonatal
endocarditis has been slow. The literature com-prises
multiple case reports representing a diversi-ty
of pathology and nomenclature. However, many
of the early reports did not include adequate peri-natal
history, microscopic examination of tissues,
gram staining, and culture techniques. Thus, it is
difficult to compare and contrast cases described as
"neonatal endocarditis" in an objective manner.
Two reviews published in 1941 and 1954 attempt-ed
to clarify the entity by reviewing its history and
adding case reports. 1•2 Despite these reports and
others published since their time, understanding
of this phenomenon is incomplete and the index of
suspicion regarding its occurrence remains low.
The following case report is of a term neonate
who succumbed during the first 24 hours of life
and was found at autopsy to have valvular lesions.
The discussion which follows delineates the spec-trum
of "endocarditis" in the neonate. We specu-late
on etiologic factors which may predispose to
the development of these lesions.
Report of case
A 3,742 gm., 0+ male was delivered to a gravida 4 pars 3
white woman via cesarean section. The 52-year-old fa-ther
had no known medical problems. The mother was
moderately preeclamptic. Fetal heart monitoring was
unremarkable except for a brief period of "grossly irreg-ular
heart rate" between 80 and 160 per minute that oc-curred
approximately 12 hours prior to delivery.
Polyhydramnios with mild meconium straining was
present at delivery. Partial placental abruption was also
noted. Apgar scores at 1 and 5 minutes were 5 and 8. The
patient was 40 weeks and appropriate for gestational
age. His color was dusky from birth. Multiple pustules
covered his trunk and extremities. Respiratory rates
were 30-60 per minute with intermittent grunting, re-tractions,
and inspiratory rales. The remainder of the
initial physical examination was normal.
The patient was placed in 75 percent 0 2 per hood.
Fluids were started via umbilical artery catheter. Bacte-rial
cultures of blood, urine, cerebrospinal fluid, and the
pustules were taken. Viral cultures were not obtained.
Ampicillin and gentamicin were begun immediately
after obtaining culture samples. One mg. of vitamin K
was administered intramuscularly.
Radiographic examination of the chest revealed a dif-fuse
interstitial process with scattered air broncho-grams.
No cardiac abnormalities were noted.
At 8 hours of life, the patient regurgitated a large
amount of dark blood and became apneic. He was subse-quently
intubated and placed on a Baby Bird ventilator.
Laboratory studies obtained at this time were as follows:
prothrombin time, 17.8 sec.; partial thromboplastin
time, 48.7 sec.; fibrinogen, 173; and the urine was large
for occult blood by dipstick method. Leukocyte count
was 13,600/cu. mm., with 3 percent band forms, 71 per-cent
segmented neutrophils, 23 percent lymphocytes,
and 3 percent monocytes. Hemoglobin and hematocrit
were 21.5 gm., and 64.5 percent respectively. The plate-let
count was 194,000/cu. mm.
Despite adequate initial blood gas levels, the patient's
respiratory status progressively worsened. The umbili-cal
artery catheter was removed at 18 hours of age be-cause
of peripheral vasospasm. A grade III/VI systolic
murmur was first appreciated at that time. The electro-cardiogram
was normal. By 20 hours of age, the pa-tient's
murmur had disappeared. He entered 2:1 atrio-ventricular
block. Progressive acidosis, hypotension,
and oliguria was unresponsive to epinephrine, sodium
bicarbonate, and atropine. The patient was pronounced
dead at 24 hours of age.
Serial platelet counts demonstrated progressive
Neonatal aseptic cardiac valvular thrombosis 399/81
Fig. 1. Aseptic thrombus of the mitral valve.
Fig. 2. Bland thrombus adherent to normal valve. (HIE stain,
45X.)
TABLE 1. SYNONYMS FOR ASEPTIC CARDIAC VALVULAR THROMBO-SIS
IN THE LITERATURE.
Synonym	 Reference no.
Neonatal endocarditis	 12
Neonatal nonbacterial thrombotic
endocarditis
	 22
Nonbacterial thrombotic vegetations	 23
Terminal endocarditis	 31
Marantic endocarditis
	 32
Disseminated intravascular and cardiac
thrombosis
	 21
Acute verrucous endocarditis	 11
Endocarditis simplex	 31
Degenerative verrucal endocarditis	 31
Toxic noninfective endocarditis	 2
thrombocytopenia. The final antemortem blood count
revealed the following: 21,700 leukocytes/cu. mm., with
7 percent band forms, 43 percent segmented neutro-phils,
35 percent lymphocytes, 10 percent monocytes, 3
percent eosinophils, 2 percent basophils; hemoglobin,
19.3 gm., hematocrit, 60.1 percent; platelet count
26,000/cu. mm. No burr cells or cell fragments were
present on the final peripheral smear.
At autopsy, the heart was without congenital defect.
The ductus arteriosus was dilated. The papillary muscu-lature
was intact. Verrucous-like lesions were present
on the atrial side of both the mitral and tricuspid valves
(Fig. 1). The two tricuspid lesions measured 9 mm. and 2
mm. in diameter. The mitral valve lesion measured 3
mm. in diameter. Microscopic examination of the vege-tations
demonstrated fibrin and platelets with scattered
groups of neutrophils (Fig. 2). There was early-stage re-active
fibrosis at the valvular level.
The lungs were grossly hemorrhagic and firm in con-sistency.
Microscopically, pulmonary edema with hya-line
membrane formation was present. Rare arteriolar
thrombi were noted.
The liver and abdominal viscera were markedly con-gested
without evidence of inflammation. No thrombi
were present in the hepatic, splenic, or renal vascula-ture.
Microscopic architecture of the thymus was nor-mal.
The brain was not examined.
All premortem and postmortem cultures were nega-tive.
Discussion
This patient expired as a result of progressive
respiratory failure associated with pulmonary
hemorrhage and hyaline membrane formation.
Progressive thrombocytopenia in the absence of
cell fragments or elevated coagulation parameters
may represent a distinctive coagulopathy associat-ed
with this syndrome.' The topical culture-nega-tive
lesions appeared clinically to represent pustu-lar
melanosis. Significant congenital heart disease
was not documented. The role that the verrucous
lesions on the tricuspid and mitral valves played
in the patient's demise is obscure.
Olney and associates reported the case of a 47-
year-old woman with aseptic cardiac valvular
thrombosis (ACVT) and malignant disease who
succumbed secondary to a cerebral embolism.4
Coronary emboli leading to myocardial infarction
have been reported by Fayemi. 5 In fact, emboli
have been noted in most major organs and ves-sels.
6 In this case, scattered thrombi were present
in pulmonary arterioles. The condition of the brain
is unknown.
The case demonstrates a form of aseptic cardiac
valvular thrombosis which has been described in
the literature under various names (Table 1). The
lesion is a bland thrombus devoid of significant in-flammatory
response (Figs. 1 and 2). It is composed
of fibrin with scattered areas of platelets and neu-trophils.
Endocarditis is a poor generic label for
this condition because of its histologic nature and
distinctive clinical presentation. A more appropri-ate
and descriptive term for the condition would be
"aseptic cardiac valvular thrombosis."
The lesion is distinctly different from the con-genital
valvular deformities previously describ-ed.
7-1° These fibroelastic hamartomas, or papillary
400/82
	
Feb. 1983/Journal of A0A/vol. 82/no. 6
fibroelastomas, are hamartomas of normal valvu-lar
tissue in an abnormal arrangement." Their
appearance differs markedly from verrucae. These
feathery pedunculated lesions, composed of elas-tin,
are quite similar to the valvular excrescences
described in 2 percent of postmortem specimens by
Blood cysts are dark red, elevated, circum-scribed
nodules found in 25-95 percent of neonatal
autopsies." These lesions are felt to be congenital
angiomas, hematomas, vascular ectasias, or mi-croextravasations
caused by "back pressure."
While blood cysts have been reported in patients
who also had ACVT, there appears to be no etiolog-ic
correlation.
Septic vegetations have been reported on neona-tal
heart valves. They appear histologically simi-lar
to ACVT with the exception that organisms are
present in the lesion. It has been hypothesized that
the genesis of septic vegetation is in the antemor-tem
formation of ACVT.12
Clinically, septic endocarditis appears to affect
neonates who have attained at least 5 days of
life. 13-16 This contrasts with the early onset and
rapid evolution of ACVT. Neonates with septic en-docarditis
often demonstrate a well-documented
extracardiac locus of infection, such as meningitis,
pneumonia, osteomyelitis, pyoarthritis, bactere-mia,
and skin infection.2,13,14,17,18 This is not dem-onstrated
in cases of ACVT. Cases of septic endo-carditis
have been reported both with and without
congenital cardiac defects. 1536 It is well accepted
that congenital heart lesions predispose to bac-terial
endocarditis in later childhood. 19,23 We
agree with Johnson's conclusion that "congenital
heart disease does predispose to endocarditis in in-fancy."
14
ACVT appears to occur in a distinct segment of
the neonatal population. Table 2 compares 14
cases reported to date. Several case reports suggest
a relationship between maternal infection and
ACVT. 12•21 Six of 9 cases in which a comment was
made regarding maternal history manifested pree-clampsia.
Meconium was invariably present in the
amniotic fluid. In Favara's excellent study, "Ba-bies
with cardiac thrombosis were larger, of more
advanced gestational age, were admitted earlier
and died sooner than babies in the control se-ries."
22 Platelet counts were below 30,000/cu. mm.
in 3 of 4 cases with a value reported. Other than
patent foramen ovale and ductus arteriosus, con-genital
heart defects are rare. A murmur is vari-ably
present and an umbilical venous or arterial
catheter is commonly used.
The etiology of ACVT is unknown. Various
events have been cited as etiologic factors. These
include polycythemia, disseminated intravascular
coagulation, intracardiac placement of umbilical
venous catheters, hypoxia, and altered hemo-dynamics.
13,22 -27 Table 3 summarizes factors
which may contribute to the genesis of ACVT. A
recently published report supports the altered he-modynamics
theory by documenting an increased
incidence of persistent fetal circulation associated
with ACVT.3
The common association with thrombocytopenia
and the fibrinoid morphology suggest that ACVT
may be a manifestation of a consumptive coagulo-pathy,
disseminated intravascular coagulation
(DIC). Boyd reported this association in 1965 and
1967.25." Kim studied 36 adults with ACVT and
found postmortem evidence of DIC in 50 percent of
the cases." An autopsy series at the University of
Zurich corroborated these results." Numerous
other authors have postulated a relationship be-tween
ACVT and the hypercoagulable state, espe-cially
in patients with malignant disease.30•31
While DIC may result in ACVT among adults, this
association has not been substantiated in new-borns.
Favara and Morrow provide evidence that
thrombocytopenia is the major manifestation of a
distinctive coagulopathy associated with ACVT.3•22
To date, the diagnosis of ACVT has not been
made antemortem. Echocardiography has been
used recently to demonstrate septic vegetations as
small as 0.7 cm. in the living neonate. 16- 18 Thus,
given a high index of suspicion, it is now possible
to make the diagnosis of ACVT prior to death.
Appropriate specific therapy for ACVT is un-known.
Meticulous attention to supportive care
and associated problems offer the best chances for
survival. It is hoped that recognition during life
and improved intensive care will provide illumina-tion
of the causes, course, and therapy of this disor-der.
1. Gross, P.: Concept of fetal endocarditis. General review with report of
illustrative case. Arch Pathol 31:163-77, Feb 41
2. Macaulay, D.: Acute endocarditis in infancy and early childhood. Am
J Die Child 88:715-31, Dec 54
3. Morrow, W.R., Hasa, J.E., and Benjamin, D.R.: Nonbacterial endo-cardial
thrombosis in neonates. Relationship to persistent fetal circula-tion.
J Pediatr 100:117-22, 1982
4. Olney, B., et al.: The consequences of the inconsequential. Marantic
(nonbacterial thrombotic) endocarditis. [clinical conference) Am Heart J
98:513-22, Oct 79
5. Fayemi, A.O., and Deppisch, L.M.: Coronary embolism and myocardi-al
infarction associated with nonbacterial thrombotic endocarditis. Am
J Clin Pathol 68:393-6, Sep 77
6. Dudley, H.R., Goodale, F., Jr., and O'Neal, R.M.: Fibro•elastic ha-martomas
of heart valves. Am J Pathol 32:35-9, Feb 56
7. Deppisch, L.M., and Fayenu, A.: Nonbacterial thrombotic endocardi-tis.
Clinicopathologic correlations. Am Heart J 92:723-9, Dec 76
Shub, C., et al.: Cardiac papillary fibroelastomas. Two-dimensional
echocardiographic recognition. Mayo Clin Proc 56:629-33, Oct 81
9. Pomerance, A: Papillary "tumours" of the heart valves. J Path Bact
81:135-40, Jan 61
Neonatal aseptic cardiac valvular thrombosis
	 401/83
TABLE 2. CASES OP NEONATAL MEW CARDIAC VALVULAR THROMBOSIS mown TO DAM
Cases, da
and refer-te
Weight Age at Umbilical
Moe no.	(grams) death Hematocrit Murmur catheter
Lowest
platelet Cardiac
count endings
Macula=
staining
Maternal
compliddions
Plant and 1,182 11/2 hrs. NR NR NR NE Blood cysts NE Habitual abetter
Sharnoff," Mild infinema
1935
Plant," NR 24 hrs. NR NR NR NE Blood cysts NR Ptudampsia
1999 Premature rupture
cemembnutes
McDonald," 2,135
1960
17 hrs. NR +Systolic NR NE Patent ductue
artwiosus
NR Syphilis
Patent bums.
ovals
Oppenheimer 3,130
and Easterly"
1,758
27 hrs.
11 days
• NR
NR
NE
NR
NE Blood cysts
NR Ventricular
espial defect
NR
NE
NR
NB
Blood cysts
B00.2636
1965 and 2,650 211/2 hrs. NR +Systolic NR PM Normal NE Hypertension
1967 Chronic bronchitis
Ward," 1971 3,133 40 bra. NR NR NR NR Normal NR Prochmipsia
Chronic bronchitis
Faevtazi2 1,600 72 hrs. 81
percent
NB 25,000	Normal Hypertension
2,960 72 hrs. 59.2
percent
NE + "Adequate Normal Diabetes mellitus
Hyputonsion
2,600 9 days 49
percent
NR + 'Adequate" Normal NR None
Krouse" 3,340
1979
30 hrs. 73
percent
No NR 22,000/ Patent ductus
on. mm. arteriosus
NR
Patent fanunen
ovals
2,810 30 hrs. 56
percent
+Systolic + 279,000/ Patent ductus
cu. mm. arterioles'
NR NR
McGuiness," 2,600
et al., 1980
32 hrs. NR NR NR Normal NE
Marino and 3,742
Robbins,"
24 hrs. 64.6
percent
+Systolic + 26,0001 Patent ductus
cu. mm. arterionts
+ Preedampsia
1981
'Although no number was given, the authors commuted that the "red cell volume we. elevated.'
Key: + - Present
– - Absent
NR - Not Reported
TABLE 3. POSSIBLE CONTRIBUTING FACTORS IN ASEPTIC CARDIAC
VALVULAR THROMBOSIS.
Prenatal and perinatal Postnatal
Maternal infection Polycythemia
Stressful labor Disseminated intravucular
coagulation
Preeclampsia Umbilical venous catheter
Meconium Altered hemodynamics
Large•term baby
10. Lambl, V.A.: Papilla's exaucensen an der semilunar•klappe der
aorta. Wein Med Wochenschr 8:244-7,1888
11. Levinson, B.A., and Learner, A.: Blood cysts on hurt valves of new-born
infants. Arch Path 14:810.17, Dec 82
12. Kunstadter, LH., and Kaltenekker, F.: Acute verrucous endear&
tie in the newborn. J Pediatr 51:5844, Jul 82
blicOuinnees, G.A., Behiektin, BM.. and Maguire, G.F.: Radeauditie
In the newborn. Am J Din Child 134:577.80, Jun 80
14. Johnsen, D.H., Reeenthal, A., and Nadu, AIL: Batted& endocerdi-tis
in children under 2 years clap. Am J Di. Child 129:1884, Feb 75
15. Bidden, L.C., et al: Bacterial endocarditis in the neonate. Am J Dim
Child 124:7474, Nov 72
111. Bender, R.L., et al.: Fahocardlographic diagnosis &bacterial undo-cuddle
of the mitre] valve in • neonate. Am J Dis Child 181:748.9, Jul
77
17. Weinberg, A.G., and Wad, W.P.: Group B standoceocal endocardi-tis
detected by echocardlography. J Pabst: 98k8854, Feb 78
18. LundstrOsn, N.R., and Mrkhem, G. Mitral and trim* valve yew
titian. in Infancy &wooed by echocardiography. Acta aediatr Stand
88:845-50, May 79
IL Johnson, D.H., Rosenthal, A., and Nadas, A.8.: A fbriryear review
of bacterial 4Indocarditis In infancy and childhood. Circulation 51:581-8,
Apr 75
90. Mendelsohn, G.. and Hutchins, GM.: Infective *adamants during
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the fret decade of life. An autopsy review of 33 cases. Am J Dis Child
133:619-22, Jun 79
21. McDonald, R.H.: Valvular thrombotic vegetation in the newborn
("fetal endocarclitie). Arch Pathol 50:538-44, Nov 50
22. Fevers, B.E., Franciosi, R.A., and Butterfield, L.J.: Disseminated
intravascular and cardiac thrombosis of the neonate. Am J Dis Child
127:197-204, Feb 74
23. Krona, H.F.: Neonatal nonbacterial thrombotic endocarditis. Arch
Pathol Lab Med 103:76-8, Feb 79
24. Oppenheimer, E.H., and Easterly, J.R.: Nonbacterial thrombotic
vegetations. Occurrence in neonate infant, and child, and relation to val-vular
lesions in cardiac defects. Am J Pathol 53:63-81, Jul 68
25. Boyd, J.F.: Disseminated fibrin thrombo-embolism among still-births
and neonatal deaths. J Path Bact 90:53-63, Jul 65
28. Boyd, J.F.: Disseminated fibrin thromboembolism among neonates
dying within 48 hours of birth. Arch Dis Child 42:401-9, Aug 67
27. Symchych, P.S., Krauss, A.N., and Winchester, P.: Endocarditis fol-lowing
intracardiac placement of umbilical venous catheters in neo-nates.
J Pedlar 90:287-9, Feb 77
28. Kim, H.S., et al.: Nonbacteria thrombotic endocarditis (NBTE) and
disseminated intravascular coagulation (DIC). Arch Pathol Lab Med
101:65-8, 1977
29. Scherer, P., and Schneider, J.: Thrombotic endocarditis and its cor-relation
to disseminated intravascular coagulation. Schweiz Med Wo-chenachr
108:744-50, 1978
30. Amundsen, M.A., et al.: Hypercoagulability associated with malig-nant
disease and with the postoperative state. Evidence for elevated lev-els
of antihemophilic globulin. Ann Intern Med 58:608-16, Apr 63
31. Heofer, W.: Hypercoagulability and verrucous endocarditis associat-ed
with adenocarcinoma of the lung. Ann Thorac Surg 6:181-6, 1968
32. Allen, A.C., and Sirota, J.H.: Morphogenesis and significance of de-generative
verrucal endocardiosis (terminal endocarditis, endocarditis
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55, Nov 44
33. Hudson, R.B.: Lambl's excrescences and nonbacterial vegetations on
heart valves. Cardiovascular Pathology 2:1260-4, 1965
34. Plant, A., and Sharnoff, G.: Acute valvular endocarditis in the new-born.
Arch Pathol 20:582-6, 1935
35. Plant, A.: Active endocarditis in the newborn. Am J Pathol 15:649-
50, 1939
38. Ward, A.M.: Endocarditis in the neonatal period. Arch Dis Child
46:731-3, Oct 71
37. Marino, R.V., and Robbins, D.A.: Neonatal aseptic cardiac valvular
thrombosis—An evolving syndrome: Report of case. JAOA 82:399-403,
Feb 83
Accepted for publication in June 1982. Updating, as necessary,
has been done by authors.
Dr. Marino is assistant professor in the Department of Pediat-rics
at the University of Medicine and Dentistry of New Jersey,
New Jersey School of Osteopathic Medicine, Camden, New
Jersey. Dr. Robbins is a clinical associate professor at Ohio
University College of Osteopathic Medicine, Athens, Ohio. He
is in the private practice of pediatrics in Columbus, Ohio.
Dr. Marino, Department of Pediatrics, University of Medicine
and Dentistry of New Jersey, New Jersey School of Osteopath-ic
Medicine, Medical Arts Building, 300 Broadway, Camden,
New Jersey 08103.
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