Bereczky, Zsuzsanna

Kerényi, Adrienne

Kiss, Csongor

Kovács, Tamás

Mogyorósy, Gábor

Nagy, Andrea

Szöllősi, Zoltán

Cardiologia Hungarica

University of Debrecen Electronic Archive

Cardiologia Hungarica 2011; 41 : 14–X
© 2011 Locksley Hall MediaCase report
Unfractionated heparin and long-term oral anticoagulation resulted in a
disappearance of a left ventricular thrombus in a 2-year-old girl with dilated
cardiomyopathy. One month later biventricular thrombosis developed in spite of
oral anticoagulation. High-dose heparin and oral anticoagulation were applied
with success. Nine months after discharge, the antithrombin activity was
repeatedly subnormal (49%). The genetic analysis did not reveal any mutation
responsible for antithrombin deficiency. There are no prospective controlled trials
proving the benefits of anticoagulation in patients with DCM and sinus
rhythm. Besides monitoring ventricular enlargement and dysfunction, the
investigation of natural anticoagulant systems may identify a subgroup of
patients at risk for developing ventricular thrombi and thromboembolism.
Recurrent Intraventricular Thrombosis
in a Child with Dilated Cardiomyopathy and
Antithrombin Deficiency
Gábor Mogyorósy1,
Tamás Kovács1,
Andrea Nagy1,
Adrienne Kerényi2,
Zoltán Szöllõsi3,
Zsuzsanna Bereczky4,
Csongor Kiss1
1Institute of Pediatrics, Medical and
Health Science Center, University
of Debrecen, Hungary
2Department of Clinical
Biochemistry and Molecular
Pathology, Medical and Health
Science Center, University of
Debrecen, Hungary.
3Department of Pathology,
Medical and Health Science Center,
University of Debrecen, Hungary
Clinical Research Center,
Medical and Health Science Center,
University of Debrecen, Hungary
Correspondence to:
Gábor Mogyorósy, MD, PhD
Institute of Pediatrics,
University of Debrecen
Nagyerdei krt. 98. Debrecen,
P.O. Box: 32
H-4012, Hungary.
Tel.: +36-52414992
Fax: +36-52414992
E-mail: mogyoros@dote.hu
Cardiologia Hungarica 2011; 41 : 14
Keywords: 
intracardiac thrombosis, dilated
cardiomyopathy, antithrombin deficiency, child
Intracardiac thrombosis is a well-known complicationof dilated cardiomyopathy (DCM). Systemic or pul -
monary embolization contributes significantly to mor -
bidity and mortality of DCM in childhood (1). Central
nervous system (CNS) embolization is the most
common manifestation of systemic emboli zation, and
may lead to significant morbidity and mortality. CNS
embolization is commonly seen without echocar dio -
graphic signs of intracardiac throm bosis (2). Anti -
coagulation may prevent throm bo em bolic events.
However, except in patients with previous throm bo -
embolic event, atrial fibrillation and newly formed left
ventricular thrombus, currently available evidence is
inconclusive whether or not the benefits of anti coa -
gulation therapy outweigh its risks in other subgroups
(3, 4).
DCM associated with acquired or congenital disorders
of the natural anticoagulation systems including
G1691A Factor V Leiden mutation, prothrombin
G20210A mutation, protein C, protein S and anti -
throm bin (AT) deficiency may represent another
subgroup of patients who may benefit from oral
anticoagulation therapy. Supporting this view we
present the case of a 2-year-old girl with DCM and
antithrombin deficiency that had recurrent intracardiac
thrombosis. 
Case Report
DCM was diagnosed in a two-year-old girl by non-
invasive methods (ECG, echocardiography, laboratory
tests). The fractional shortening of the left ventricle was
13% as checked by echocardiography. Introduction of
furosemide, digoxin and enalapril resulted in an impro -
vement in the circulatory condition of the patient. Ho -
wever, nine months later pallor and tachypnea developed.
Chest x-rays showed extreme cardiomegaly, atelectasis of
the left lung and pleural effusion requiring drainage. A
thin-cut spiral computer tomograph (CT) scan revealed a
large flat, non-pedunculated thrombus in the left ventricle
(Fig. 1) and also showed a compression of the left main
bronchus by the enlarged heart resulting in atelectasis. The
fractional shortening of the left ventricle was 7% as checked
by echocardiography.
Unfractionated Na-heparin infusion was started at a
loading dose of 50 U/kgbw and maintained for four days
at a dose of 45-50 U/kgbw/hr followed by a gradual switch
to oral anticoagulation (acenocoumarol 1 mg daily). He -
parin treatment resulted in only a moderate prolongation
of activated partial thromboplastin time (aPTT) (patient:
46.3 s, control: 33.3 s). The intracardiac thrombus, mo ni -
tored by transthoracic echocardiography shrank gradually
(Fig. 2A) and disappeared completely after 20 days (Fig.
2B). No clinical symptoms, indicating an embolic event
were detected. The patient was discharged and remained
Mogyorósy et al: Recurrent Intraventricular Thrombosis
Cardiologia Hungarica 2011; 41 : 15
Figure 1. (A) Contrasted spiral CT scan of the heart: large flat thrombus (arrow) attached to the
posterior wall of the left ventricle. (B) Left lung atelectasis owing to the compression of the left main
bronchus (arrow)
Figure 2. (A) Four chamber view 2D echocardiogram: the left ventricular thrombus (arrow) diminished in
size compared to the CT scan. (B) Four chamber view 2D echocardiogram: no thrombus can be detected
A B
A B
on oral anticoagulation therapy (acenocoumarol 1 mg
daily). INR values fluctuated between 1.77 and 4.65,
possibly because of her unstable circulatory state. Thirty-six
days after discharge, intracardiac thrombi were detected
again in both ventricles by echocardiography. The left
ventricular function, measured by echocardiography, was
poor (fractional shortening 6%). We started unfractionated
Na-heparin infusion again, but large doses (45-50
U/kgbw/hr) were required to maintain an acceptable anti -
coagulation effect (patient aPTT/reference aPTT³1.5).
AT measurement by a chromogen test revealed reduced
activity with 55% (reference value: 80-120%). Nineteen
days later a transthoracic echocardiography indicated the
disappearance of the thrombi. The patient was discharged
again on oral anticoagulation (acenocoumarol 1 mg daily).
The hemostasis was checked nine months later (Table 1).
AT activity was repeatedly subnormal (49%). The patient
did not have either a Factor V Leiden or a prothrombin
G20210A mutation. Protein C and S activities were not
determined because of vitamin K antagonist therapy (Tab -
le 1). At this time, the circulatory condition of the patient
was relatively stable.
No thromboembolic event occurred in the parents and
grandparents. The mother had no miscarriage. The child
had one female sibling who was healthy. We were not able
to determine AT levels in the parents and the sibling.
One year later the patient was hospitalized again suffering
from severe congestive heart failure due to a progressive
deterioration of left ventricular function. In spite of in -
tensive treatment the child died at the age of five, two-and-
a-half years after the diagnosis of DCM. Autopsy con fir -
med the presence of dilated cardiomyopathy associated with
endocardiac fibroelastosis and the complications of severe
congestive heart failure. However, the autopsy did not re -
veal any evidence of thromboembolic complications. We
have sequenced AT gene, and found only three common
polymorphisms. The first was a guanine-adenine
(GTG®GTA) change at nucleotide 8130, the second was
a guanine-adenine (CAG®CAA) change at nucleotide
8160 and the third was a thymine-cytosine (GTT®GTC)
change at nucleotide 8199. No mutation, responsible for a
genetic AT deficiency was found.
Discussion
The incidence of thromboembolism in children with
DCM is 4%-16% (1, 3, 5–8). The most important pre -
disposing factor is slow blood flow owing to impaired
systolic function. According to Falk et al, a fractional
shortening of less than 10% seems to be a risk factor
(5). Our patient had a fractional shortening of 13% at
the time of diagnosis. Günthard et al reported that a
fractional shortening of less than 20% may already
result in stasis and intracardiac thrombi in children (1).
This study, involving a few number of children,
suggested that long-term anticoagulation therapy may
prevent the recurrence of thrombotic and embolic
events (1). In our patient, oral anticoagulation did not
prevent repeated thrombus formation.
The recurrence of intraventricular thrombi may be
explained by a number of factors in the presented case.
x The dose of acenocoumarol did not result in a
permanently effective anticoagulation as checked by
the INR values.
x The ventricular function of the patient deteriorated
progressively.
x The patient exhibited repeatedly diminished AT
activity.
Congenital and acquired disorders of the natural anti -
coagulant systems increase the risk of clot formation
(9, 10, 11). Intracardiac thrombosis in association with
congenital or acquired protein C deficiency, Factor V
Leiden, and prothrombin G20210A mutations have
already been published (9, 10, 11).
Our patient required large doses of unfractionated
heparin to achieve an aPTT within the therapeutic
range. Besides AT deficiency several mechanisms for
heparin resistance have been identified including in -
creased heparin clearance, elevation in heparin-binding
pro teins and elevations in factor VIII levels and
fibrinogen levels (12). There is evidence in adults with
thrombosis and heparin resistance, that therapeutic
levels of heparin as measured by the anti-factor Xa
assay may be clinically efficacious even though the
aPTT is subtherapeutic (13).
Mogyorósy et al: Recurrent Intraventricular Thrombosis
Cardiologia Hungarica 2011; 41 : 16
Table 1. Characterization of the hemostatic sys -
tem of the patient 9 months after the second
thrombotic event
*Protein C and S levels were not determined (n.d.) because of
acenocoumarol therapy.
Tests Patient Control/
Reference
values
Prothrombin time (sec.) 25.6 s 9.2-11.5 s
INR 2,4
Activated partial 
thromboplastin time (aPTT)
42.4 s 27.8-42.8 s
Thrombin time (TT) 17.1 s 15.4-23.4 s
Antithrombin-III activity 49% 80-120%
Protein C* activity n.d. 70-130%
Protein S* activity n.d. 65-140%
Plasminogen activity 89% 80-120%
Activated Protein C ratioe 2,25 >2,0
Factor V Leiden-mutation wild type wild type
Prothrombin 20210G A
mutation
wild type wild type
Fibrinogen 3,97 g/l 1,5-4,0 g/l
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between intracavitary thrombosis detected by cross sectional
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bo-embolism in dilated cardiomyopathy: a prospective follow-up
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Irodalom
The potentiation of AT activity is the principle me -
chanism by which both heparin and low-molecular-
weight heparin produce anticoagulation. The relative
inefficiency of heparin treatment brought up the issue
of AT deficiency in our case. That is why the initial AT
level was drawn after heparin therapy was instituted.
Although unfractionated heparin therapy can result in
depression of the levels of AT, still we believe that our
patient had low levels of AT, as the repeated AT de -
termination when the patient was no longer on heparin
was also depressed.
Congenital AT deficiency is an autosomal dominant
disorder, associated with an increased risk of throm -
bosis, typically presenting in young adulthood. Severe
congenital AT deficiency is an autosomal recessive
condition associated with increased thrombogenesis,
typically noted in infancy. Acquired deficiencies com -
monly are due to consumption. Other reported mecha -
nisms of acquired AT deficiency include chronic liver
disease, with resultant synthesis failure, and protein loss
due to ascites or nephrotic syndrome. In our patient the
genetic analysis did not reveal any mutation responsible
for antithrombin deficiency. We consider the anti -
throm bin deficiency acquired in the presented case.
The activation of the coagulation system has been
demonstrated in adult patients with idiopathic cardio -
myopathies (14). In patients with DCM, the thrombin-
antithrombin complex levels showed a positive corre -
lation with left ventricular end-diastolic volume and a
negative correlation with fractional shortening of the
left ventricle (14). Although, a similar mechanism may
have played a role in diminished AT level, as observed
in our patient, this would not account for such a
decrease in AT level. Erbay et al (15) did not find
antithrombin deficiency in patients with or without
ventricular thrombus and dilated cardiomyopathy. Pre -
sent literature data are inconsistent whether individuals
with DCM and antithrombin deficiency at a higher
risk than those with DCM alone. Our study implicates,
that further investigations could establish whether
acquired antithrombin deficiency is an independent
risk factor in patients with DCM.
Our observations and other studies underline the need
for characterizing the activation of platelets (16), the
coagulation and fibrinolytic systems in children with
DCM (10, 11, 14). A recent guideline on antithrombotic
therapy in children (17) suggests vitamin K-antagonist
therapy in children with DCM should begin no later
than when the child is activated on a cardiac transplant
waiting list. Probably, more detailed recommendation
can be made if and how these patients should be anti -
coagulated to decrease the incidence of thrombo em -
bolic complications if hemostatic markers are taken
into consideration.
Mogyorósy et al: Recurrent Intraventricular Thrombosis
Cardiologia Hungarica 2011; 41 : 17


Recurrent intraventricular thrombosis in a child with dilated cardiomyopathy and antithrombin deficiency

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Recurrent intraventricular thrombosis in a child with dilated cardiomyopathy and antithrombin deficiency

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