Thrombocytopenia in Patients with Tetralogy of Fallot

THROMBOCYTOPENIA IN PATIENTS WITH TETRALOGY OF FALLOT,

A CONDITION REQUIRING IMMEDIATE ATTENTION

Teddy Ontoseno

ABSTRACT

Background: In Indonesia, most of the patients (95%) with Tetralogy of Fallot (TF) are still faced to disadvantageous situation, since
it remains difficult for them to obtain immediate surgical corrective procedure. Delayed surgical procedure for these patients may
often lead to the occurrence of fatal complications, i.e., hemostatic function disorder and cerebrovascular accident accompanied
with thrombocytopenia. Objective: to prove the influence of arterial oxygen saturation on the development of thrombocytopenia and
to disclose correlation between arterial oxygen saturation and cut-off point and thrombocytopenia in TF patients. Methods: This was
a case control study undertaken by involving 94 patients with Tetralogy of Fallot. Patients without thrombocytopenia were assigned
as control group, while those with thrombocytopenia belonged to case group. Thrombocytopenia was determined as having 33,000 -
135,000 cells/mm3 cell dynamic. Arterial oxygen saturation was below 90% in room temperature, as measured by pulse oximetri.
Multiple logistic regression analysis, Kappa association analysis, and McNemar test were employed in this study. Results: From 47
patients studied, significant difference was found between age and thrombocytopenic development. Average age of thrombocytopenic
group was 58.81 months, and non-thrombocytopenic group was 36.19 months. Oxygen saturation of <60% was found significantly
influencing the development of thrombocytopenia. Cut-off point of arterial oxygen saturation was 57% (Kappa 9.09505 and p <
0.05). Conclusions: (1) arterial oxygen saturation influences thrombocytopenic development; (2) a negative correlation of 0.2093
exists between arterial oxygen saturation and thrombocytopenic development; (3) cut-off point of arterial oxygen saturation is 57%
with sensitivity and specificity of respectively 100% and 93.6%.

Keywords: Tetralogy of Fallot, thrombocytopenia

INTRODUCTION Abnormality in blood clotting factor, such as

Tetralogy of Fallot (TF) is a complex abnormality of
cardiac anatomic structure that develops during
intrauterine life. It is one of several cyanotic congenital
heart diseases most commonly found in infants or
children, and the third most frequent disease among all
congenital heart diseases, with the incidence rate of
10% (Therrien, 2001).
The only definitive treatment for TF is surgical
correction. In Indonesia, the procedure remains difficult
to accomplish, since quantity and distribution of human
resource and equipments to perform the operation
remain inadequate. To date, cardiac corrective surgery
can be undertaken only to 5% of all TF cases
(Ontoseno, 1999).
Lower arterial oxygen saturation often presents as the
cause of fatal complications. These complications that
mostly found at the first year of life are brain abscess,
cerebral vascular disorder presenting as bleeding or
cerebral venous disorder and cyanotic attack that may
result in permanent disability and even leads to fatal
outcome (Ontoseno, 1995).
_____________
Division of Cardiology
Department of Pediatrics
Airlangga University School of Medicine
Dr Soetomo Teaching Hospital, Surabaya
thrombocytopenia, defects in thrombocyte and
coagulative function, very likely attribute to the
occurrence of bleeding and thrombosis. Thrombotic
change observed is presenting as the alteration of its
quantity and function, with thrombocytopenic incidence
as much as 42%. However, its mechanism and
predisposing factors remain unclear (Hatthaway, 1993).
This study was aimed to investigate the influence of
arterial oxygen saturation and hematocrite on the
occurrence of thrombocytopenia in Tetralogy of Fallot
patients.
METHOD
A case control study was undertaken to TF patients
between April 2000 and January 2001. The patients,
aged from 6 months to 6 years, were those admitted at
Outpatient Clinic, Dr Soetomo Hospital. The diagnosis
of TF was established on echocardiography.
Thrombocytopenia was diagnosed if cell count was
between 33,000 and 135,000/mm3, as examined by cell
dynamic. Arterial oxygen saturation was examined by
means of pulse oxymetry, and it was considered as
lower when it was 90% under room temperature.
Sample size for case group (with thrombocytopenia)
and control (without thrombocytopenia) was determined
by the following formula:

Folia Medica Indonesiana 49 Vol. 39 No. 1 January March 2003

 Thrombocytopenia in Patients with Tetralogy of Fallot

n = 4.(Z1/2) p(1-p) correlation between arterial oxygen saturation and

W2 thrombocytopenia; Kappa association analysis and
McNemar test to determine cut-off point on arterial
p = prevalence of thrombocytopenia in TF; = 0.05; W oxygen saturation and the risk of thrombocytopenic
= absolute precision level; n = minimal sample size (47) development.

The exclusion criteria used in this study were palliative

post-operative patients and patients with severe
anatomic abnormality.
Statistical analysis employed were multiple logistic
regression test to identify the influence of arterial
oxygen saturation on thrombocytopenia; correlation
analysis to determine severity and presence of
RESULTS
From 129 patients with Tetralogy of Fallot admitted at
the Outpatient Clinic, Dr Soetomo Hospital, in 9 months
(from 1 April 2000 to 31 January 2001), 104 were
eligible to be enrolled in this study.

Table 1. Age and sex distribution of TF patients

Age Male Female

(months) Total % Total % Total %
>6 12 5 9.09 12 22.00 15 15.96
>12 24 8 15.91 10 18.00 16 17.02
>24 36 10 20.45 8 14.00 16 17.02
>36 48 6 11.36 3 4.00 7 7.45
>48 60 10 20.45 8 14.00 16 17.02
>60 72 10 22.73 15 28.00 24 25.53
Total 49 100.00 55 100.00 104 100.00

The table above shows that most of the patients are at the age of 60 to 72 years, in which 10 (22.73%) was male and 14
(28%) was female.

Table 2. Comparison of age between thrombocytopenic and non-thrombocytopenic groups

Age Thrombocytopenia Non-thrombocytopenia

(months) Total % Total % Total %
>6 12 3 4.26 14 27.66 15 15.96
>12 24 4 6.38 14 27.66 16 17.02
>24 36 10 19.15 8 14.89 16 17.02
>36 48 8 14.89 1 0.00 7 7.45
>48 60 10 19.15 8 14.89 16 17.02
>60 72 17 36.17 7 14.89 24 25.53
52 100.00 52 100.00 104 100

Using Mann-Whitney test, analysis on age in group was 58.81 months, while that in non-
thrombocytopenic and non-thrombocytopenic groups thrombocytopenic group was 36.19 months, with
revealed that the average age in thrombocytopenic significant difference of p = 0.01.

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 Thrombocytopenia in Patients with Tetralogy of Fallot

Table 3. Comparison of sex between thrombocytopenic and non-thrombocytopenic groups

Thrombocytopenia Non-thrombocytopenia
Sex Total % Total % Total %
Male 28 53.19 23 42.55 51 47.9
Female 24 46.81 29 57.45 53 52.1
52 100.00 52 100.00 104 100

Chi-Square test reveals no significant difference in sex between both groups.

Table 4. Comparison of arterial oxygen saturation in categorical data between thrombocytopenic

and non-thrombocytopenic groups

Thrombocytopenia Non-thrombocytopenia
SatO2(%) Total % Total % Total %
Male 50 100 7 10.64 57 55.32
Female 3 0 45 89.36 47 44.68
52 100.00 52 100.00 104 100
p = 0.01 (significant)
(Chi-Square test)

The table shows that in all cases with thrombocytopenia data on arterial oxygen saturation reveals significant
arterial oxygen saturation is at the category of < 60%, difference with p = 0.01 between thrombocytopenic and
while non-thrombocytopenic group mostly falls in the non-thrombocytopenic group.
category 60 - 79.9%. Chi-Square test for quantitative

Table 5. ROC of arterial oxygen saturation

Predictive Value
SatO2 Sensitivity Specificity + (%) - (%) Kappa test McNemar test
(%) (%)
50 66.0 100.0 100.0 74.6 6.80103(S) 0.0000(S)
51 74.5 100.0 100.0 79.7 7.46744(S) 0.0005(S)
52 83.0 100.0 100.0 85.5 8.16422(S) 0.0078(S)
53 89.4 97.9 97.7 90.2 8.48845(S) 0.2188(NS)
54 91.5 97.9 97.7 92.0 8.68164(S) 0.3750(NS)
55 95.7 95.7 95.7 95.7 8.87022(S) 1.0000(NS)
56 97.9 95.7 95.8 97.8 9.07856(S) 1.0000(NS)
57 100.0 93.6 94.0 100.0 9.09505(S) 0.2500(NS)
58 100.0 91.5 92.2 100.0 8.90252(S) 0.1250(NS)
59 100.0 89.4 90.4 100.0 8.71336(S) 0.0625(NS)
60 100.0 89.4 90.4 100.0 8.71338(S) 0.0625(NS)
S = significant, if z > 1.96 or p < 0.05
NS = not-significant, if z < 1.96 or p > 0.05.

Cut-off point is considered valid if the result of Kappa
Test was significant, while that of McNemar was not
significant. Cut-off point of arterial oxygen saturation
was 57%, with sensitivity of 100.0%, specificity was
93.6%, while the positive predictive value 94.0%, and
negative predictive value 100.0% with kappa value of
0.09505, which was significant (z > 1.96). Result of
McNemar test was 0.2500, indicating not significant (p
< 0.05). Arterial oxygen saturation examination
revealed an average value of 57.29 + 10.15% in all
patients, while that in thrombocytopenic group was
48.17 + 4.19% and in non-thrombocytopenic group was
66.40 + 4.58%. The average thrombocyte count in all
patients was 172.55 + 89.14% cells/mm3. In
thrombocytopenic group it was 92.36 +/- 20.11

Folia Medica Indonesiana 51 Vol. 39 No. 1 January March 2003


cells/mm3 and in non-thrombocytopenic group it was
252.74 +/- 50.18 cells/mm3.
DISCUSSION
The decrease of arterial oxygen saturation or hypoxia is
commonly found in Tetralogy of Fallot. However, the
amount of the decrease is different and it is largely
determined by the severity and progressiveness of
pulmonary stenosis. The development of
thrombocytopenia is likely due to prolonged hypoxia.
All of these factors are responsible for the uncertain
onset of thrombocytopenia.
Tetralogy of Fallot patients aged less than 6 months
were not included in this study since iron status in such
patients was still subjected to change due to the
transitional period from intrauterine life into
extrauterine life. Age of six months was used as the
limit because collateral circulation to compensate
hypoxia has not been established and thrombocytopenia
is commonly found in infants at the age of less than 1
month to 3 months (Rowe, 1978).
Results in this study showed that thrombocytopenic
population mostly belongs to age group of 60 - 72
moths, while respondents in non-thrombocytopenic
group were mostly between 6 - 12 months and 12 - 24
months (Table 5.2). Comparison of both age groups
demonstrated significant difference with average age of
58.81 months in thrombocytopenic group and 36.19
months in control group.
Above the findings correspond to the results of previous
studies, in which it was found that age was related to the
progressiveness of infundibulum spasm, and the
increase of age is along with the increasing severity of
infundibulum hypertrophy of right ventricle and the
obstruction of right ventricle outflow as well as the
reduction of blood count inflow to the lungs,
aggravating the hypoxia.
The results of this study also corresponds to the findings
of Paul et al, in which thrombocytopenia was often
found in patients of more than 1 year old, and those of
Gross (1968), where the decrease of thrombocyte count
was mostly found in patients above 3 years old. The
different of these findings from those of this study was
likely to be due to the different in severity of pulmonary
stenosis. In patients with severe pulmonary stenosis,
thrombocytopenia may manifest at earlier age compared
to that in patients with lower degree of pulmonary
stenosis.
Folia Medica Indonesiana
Thrombocytopenia in Patients with Tetralogy of Fallot
Relative anemia due to iron deficiency, an abnormality
presenting as the decrease of erythrocyte deformability
may occur, inducing rigidity in erythrocytes, resulting in
incapability to pass inside blood vessels with smaller
diameter, leading to uneven blood distribution and
contributing to the occurrence of rolleaux and elevated
blood viscosity, predisposing lysis and followed by
ADP release, stimulating the enlargement of
thrombocyte aggregation and, finally, resulting in
thrombocytopenia (Grifgoleit, 1977).
Oxygen saturation in thrombocytopenic group was
mostly less than 60%, while that in non-
thrombocytopenic group was between 60 and 79.9%.
Quantitative data showed significant difference in
arterial oxygen saturation between thrombocytopenic
group and non-thrombocytopenic group as indicated by
the results of Chi Square test comparing two or more
independent groups with categorical data (Table 5.6).
Analysis using multiple logistic Regression test reveals
that oxygen saturation of < 60% significantly influence
the development of thrombocytopenia. Analysis of
quantitative data showed that arterial oxygen saturation
had significant influence on the development of
thrombocytopenia.
These results correspond to those of previous studies
that thrombocyte count was directly correlated to
oxygen saturation (Gross, 1968). A study by
Phomphutkul et al (1973) demonstrated that TF patients
with thrombocytopenia aged more than 4 years were
more hypoxic and policytemic compared to control.
Using receiver operator characteristic, Kappa test and
McNemar test, cut-off point of arterial oxygen
saturation was found to be 57% (Kappa 0.09505 and p <
0.05), with sensitivity of 100% and specificity 93.6%,
indicating that arterial oxygen saturation below 57%
resulted in the risk of thrombocytopenic development.
Arterial oxygen saturation had acceptable sensitivity
and specificity. In other words, arterial oxygen
saturation is reliable to be used as diagnostic tool as
well as for screening test in early diagnosis of
thrombocytopenia in TF patients.
RECOMMENDATIONS
To obtain a comprehensive understanding on the
interaction of biological activity of chronic hypoxic
thrombocytic components, a study should be undertaken
on the involvement of thrombocyte biological activity in
hypoxic poliycythemia among TF patients.
1. Further studies are warranted in order to complete
the data on factors that have been discussed in
52 Vol. 39 No. 1 January March 2003

previous studies in relations with the development
of thrombocytopenia in TF patients.
2. Regular examination of peripheral blood and
arterial oxygen saturation should be undertaken, at
least once for 6 months, particularly in TF patients
who will have cardiac surgery, either definitive or
palliative, in order to obtain early detection of
thrombocytopenia.
3. Schedule and dosage of iron administration to the
patients in longer period should be monitored
closely, and an easy monitoring method should be
established, either clinical or laboratory, by
examining SI/TIBC at least once for 6 months to be
able to make an early detection of the development
of hyperviscosity syndrome, which may finally
result in thrombocytopenia in TF patients.
4. A study on the mechanism of the decrease of
erythrocyte deformability in TF patients is required,
since it may stimulate erythrocyte aggregation that
may lead to the formation of thrombus, an
important factor in the development of
thrombocytopenia.
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