Paediatrica Indonesiana

VOLUME 49 September ‡ NUMBER 5

Original Article

Effect of dengue hemorrhagic fever on

thrombomodulin level
Hendra Widjaja, Max F. J. Mantik

I
Abstract nfection of dengue virus in human may manifest
Background Thrombocyte and endothelial cells play an as dengue fever or dengue hemorrhagic fever.
important role in dengue hemorrhagic fever pathogenesis.
Thrombomodulin is a part of glycoprotein membrane in
endothelial cells. Therefore, thrombomodulin level will
increase if endothelial cells disruption occurs.
Objective 7R DFNQRZOHGJH WKH FRUUHODWLRQ EHWZHHQ WKH
degree of dengue hemorrhagic fever and thrombomodulin
level.
Methods 7KLVZDVDFURVVVHFWLRQDOVWXG\6XEMHFWVZHUH
hospitalized pediatric patients with age ranging from one
WR\HDUROGLQSHGLDWULFZDUGDW3URI'U5'.DQGRX
+RVSLWDO0DQDGRZKRKDGIHYHU7KUHHPLOOLOLWHUVRIEORRG
ZHUHWDNHQIURPYHLQDQGZHUHGLYLGHGIRUWZRWHVWVZKLFK
were routine blood analysis and thrombomodulin analysis.
'LIIHUHQWGDWDUHVXOWHGIURPWKHGHQJXHKHPRUUKDJLFIHYHU
group were processed, and analyzed statistically using F Test
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clinical features such as fever, rash, hemorrhage,
liver enlargement, ascites, and encephalopathy.
'+) JUDGH ,,, DQG ,9 DUH WKH VHYHUH PDQLIHVWDWLRQ
of this disease. Until now, there are several theories
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LPPXQRSDWKRORJ\ DQWLJHQDQWLERG\ FRPSOH[
endothelial cells and thrombocyte, also apoptosis.
Thrombocyte and endothelial cells are predicted
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Manifestations such as thrombocytopenia and
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there is impairment in integrity of endothelial cells.
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between dengue hemorrhagic fever and thrombomodulin
was analyzed with Spearman correlation coefficient.
Results There was a significant result in the difference of
thrombomodulin level on four dengue hemorrhagic fever
groups which were classified according to the severity of
dengue hemorrhagic fever. There was a very significant
positive correlation between the severity of dengue
hemorrhagic fever and thrombomodulin level in detecting
endothelial cells impairment.
Conclusion Thrombomodulin level can be used as a
PDUNHUWRGHWHFWHQGRWKHOLDOFHOOVLPSDLUPHQWLQGHQJXH
KHPRUUKDJLF IHYHU +LJKHU JUDGH RI GHQJXH KHPRUUKDJLF
fever will have higher thrombomodulin level. [Paediatr
Indones. 2009;49:259-63].
Keywords: dengue hemorrhagic fever, thrombo-
modulin, endothelial cells
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united function in maintaining homeostasis. If one of
the components is damaged, it will affect the other.
Thrombocyte has another function as secretory cell
which has granules containing various mediators.
Endothelial cells have numerous receptors, besides
producing vasoactive products such as prostacyclin,
)URPWKH'HSDUWPHQWRI&KLOG+HDOWK0HGLFDO6FKRRO6DP5DWXODQJL
8QLYHUVLW\3URI5'.DQGRX*HQHUDO+RVSLWDO0DQDGR,QGRQHVLD
Reprint request to:+HQGUD:LGMDMD0''HSDUWPHQWRI&KLOG+HDOWK
0HGLFDO6FKRRO6DP5DWXODQJL8QLYHUVLW\3URI5'.DQGRX*HQHUDO
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 )D[  (PDLO hw_230670@yahoo.co.id,
h3nw1@doctor.com
Paediatr Indones, Vol. 49, No. 5, September 2009‡259
 Hendra Widjaja et al: (IIHFWRI'+)RQWKURPERPRGXOLQOHYHO

platelet activating factor 3$)SODVPLQRJHQIDFWRU 'HVFULSWLYH DQDO\VLV DQG 6SHDUPDQ·V 5KR FRUUHODWLRQ
LQWHUOHXNLQDQGWKURPERPRGXOLQ(QGRWKHOLDOFHOOV analysis were used in this research. All of the obtained data
disruption results in thrombocyte aggregation and ZHUHSURFHVVHGE\XVLQJ6366YHUVLRQ'DWDUHVXOWVKDG
activates coagulation. DFRQILGHQFHLQWHUYDO&,DQG3
Thrombomodulin concentration on endothelial
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WUDWLRQ LV UHODWHG WR PDVVLYH EOHHGLQJ 'HQJXH YLUXV Results
will immediately activate primary pathogenesis, direct
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by activating procoagulant hemostatis mechanism. FRQVLVWHGRIVXEMHFWVLQLQWHQVLYHFDUHURRP,&8
(QGRWKHOLDOSURWHLQ&UHFHSWRU(3&5KDVDQLPSRUWDQW
UROHLQFRQWUROOLQJWKHDFWLYLW\RI&SURWHLQ%\DGGLQJ
PRQRFORQDODQWLERG\LWZLOOEORFNWKH&SURWHLQELQGLQJ
LQ(35ZKLFKZLOOUHVXOWLQKLJKHUULVNRIGHDWK
Methods
This research used analytical observation method
ZLWK FURVVVHFWLRQDO DSSURDFK RQ DOO '+) FDVHV
DQGVXEMHFWVLQSHGLDWULFZDUGIrina E3URI'U
5' .DQGRX +RVSLWDO 0DQDGR )URP  VXEMHFWV
VXEMHFWVZHUHGLDJQRVHGZLWK'+)JUDGH,HLJKW
ZLWK'+)JUDGH,,HLJKWZLWK'+)JUDGH,,,DQGVL[
ZLWK'+)JUDGH,92QGDLO\REVHUYDWLRQRQHSDWLHQW
LQ'+)JUDGH,,,JURXSKDGPHOHQDDQGRQHSDWLHQW
ZLWK'+)JURXS,9GLHG
7KHORZHVWWKURPERPRGXOLQOHYHOZDVQJ
POZKLOHWKHKLJKHVWZDVQJPO7KHPHDQYDOXH
RIWKURPERPRGXOLQOHYHOZDVQJPO7KHOHYHO
LQ SHGLDWULF ZDUG Irina E 3URI 'U 5' .DQGRX RIWKURPERPRGXOLQEDVHGRQWKHVHYHULW\RI'+)LV
+RVSLWDO0DQDGRIURP-XQHXQWLO1RYHPEHU shown in Table 1.
6XEMHFWV ZHUH DOO KRVSLWDOL]HG SHGLDWULF SDWLHQW ZLWK The mean level of thrombomodulin in four groups
age ranging from one to 13 years old in pediatric ward IURP JUDGH , WR ,9 VKRZHG WKDW WKHUH ZDV D YDVW
Irina E3URI'U5'.DQGRX+RVSLWDO0DQDGRZKR
had fever. The data were obtained from anamnesis,
physical examination, routine blood analysis, and
thrombomodulin examination using ELISA method.
The inclusion criteria were children aged one
HQGRWKHOLDOGLVUXSWLRQ+LJKHUVHYHULW\RI'+)UHVXOWHG
in higher level of thrombomodulin. Thrombomodulin
level is being used as a probe to detect endothelial cells
disruption, which can be seen on Figure 1.
The difference of thrombomodulin level in the
WR\HDUVROGZKRZHUHGLDJQRVHGZLWK'+)EDVHG IRXUJURXSVJUDGH,WR,9KDGDVLJQLILFDQWGLIIHUHQFH
RQ  :+2 FULWHULD DQG ZKRVH SDUHQWV DJUHHG
to participate in this study by filling the research
form. Exclusion criteria were children with malaria,
disseminated intravascular coagulation, diabetes
PHOOLWXV.DZDVDNLGLVHDVHDFXWHJORPHUXORQHSKULWLV
and systemic lupus erythematosus.
There were two types of variable in this research,
ZLWK)WHVW3DVVKRZQLQTable 2.
The result of thrombomodulin level was used
to detect endothelial cells disruption, as shown in
Table 3.
The correlation between thrombomodulin level
DQGVHYHULW\RI'+)ZDVDQDO\]HGXVLQJ6SHDUPDQ·V
Rho coefficient analysis. Based on this analysis, the
LHQRQGHSHQGHQWYDULDEOHWKHVHYHULW\RI'+)DQG correlation coefficients were rs 3
GHSHQGHQW YDULDEOH WKH OHYHO RI WKURPERPRGXOLQ From these results, there was a very significant
positive correlation between the increasing severity
Table I. Trombomodulin level in DHF patient
95% for CI Mean
Lowest level Highest level
N Mean SD LB UB (min) (max)
DHF I 25 6.0092 2.15445 5.2099 6.9885 3.04 8.93
DHF II 8 9.5513 0.95511 8.7528 10.3497 7.29 10.42
DHF III 8 10.1925 1.82806 8.6642 11.7208 7.91 12.61
DHF IV 6 14.3150 5.80181 8.2264 20.4036 6.86 22.61
Total 47 8.4323 3.86738 7.2968 9.5678 3.04 22.61

260‡Paediatr Indones, Vol. 49, No. 5, September 2009

 Hendra Widjaja et al: (IIHFWRI'+)RQWKURPERPRGXOLQOHYHO

DHF I DHF II DHF III DHF IV

Discussion
16.00

In this study, we tried to find the correlation between

14.00 WKURPERPRGXOLQOHYHODQGVHYHULW\RI'+)%XWWKHS
et al performed a study on thrombomodulin level by
12.00
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RIWKURPERPRGXOLQZHUH6'LQ'+)JUDGH
10.00
,6'LQ'+)JUDGH,,DQGLQGHQJXH
VKRFNV\QGURPH$VWXG\E\:LOOVHWDO, in Vietnam,
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8.00
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6.00
RIQJPO
DBD I DBD II DBD III DBD IV
In this study, the mean level of thrombomodulin
Figure 1. Thrombomodulin level on DHF in the four groups from grade I to IV showed that
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Table 2. The ANOVA Using F Test
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Sum of The difference of thrombomodulin level from the
db Squares Variance F P
Between Groups 3 378.5 126.2 17.531 < 0.0001
four groups had a significant different with F test
Within Group 43 309.5 7.2 3
Total 46 688.0 3.86738 Butthep et al  showed that the value of
Table 3. .GCUV5KIPKſECPV&KHHGTGPEGVGUVTGUWNV
WKURPERPRGXOLQRQGHQJXHVKRFNV\QGURPHLQFUHDVHG
IURPGD\²XQWLOGD\DQGWKHUHZDVDVLJQLILFDQW
Control Group
DHF Grade
Difference p GLIIHUHQFH3ZLWK:LOFR[RQWHVW
I II 3.45 0.003
The mean value of thrombomodulin level to
III 4.09 0.001 GHWHFW HQGRWKHOLDO FHOOV LPSDLUPHQW 3
IV 8.22 <0.0001 LQ '+) JUDGH , FRPSDUHG ZLWK '+) JUDGH ,, ZDV
II III 0.64 0.635
IV 4.76 0.002
 FRPSDUHG ZLWK '+) JUDGH ,,, ZDV  DQG
III IV 4.12 0.007 FRPSDUHG ZLWK '+) JUDGH ,9 ZDV  7KRVH
YDOXHVKDGDVLJQLILFDQWGLIIHUHQFH3XVLQJ
RI '+) DQG WKURPERPRGXOLQ OHYHO LQ GHWHFWLQJ /6'WHVWDQDO\VLV:KLOHFRPSDULVRQEHWZHHQ'+)
endothelial cells disruption. This correlation is shown JUDGH,,ZLWKJUDGH,,,'+)ZDVDQGWKHUHZDV
by graphic in Figure 2. DVLJQLILFDQWGLIIHUHQFH3E\XVLQJ7WHVW
7KHFRPSDULVRQEHWZHHQ'+)JUDGH,,DQGJUDGH,9
ZDVDQGWKHUHZDVDOVRDVLJQLILFDQWGLIIHUHQFH
TM = 3.64 + 2.53 * D 3E\XVLQJ7WHVW7KHFRPSDULVRQEHWZHHQ
20.00 Rs = 0.755 (p<0.001)
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15.00 test.
The level of thrombomodulin will rise on dengue
TM

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found that there was increasing level of thrombomodulin
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a sign for endothelial cells impairment led to plasma
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Figure 2. The correlation between thrombomodulin LQWR IRXU JUDGHV +LJKHU JUDGH RI '+) UHVXOWV LQ
level and DHF severity PRUH YDVW OHDNDJH RI SODVPD DV VHHQ LQ KLJKHU

Paediatr Indones, Vol. 49, No. 5, September 2009‡261

 Hendra Widjaja et al: (IIHFWRI'+)RQWKURPERPRGXOLQOHYHO
level of thrombomodulin level. The correlation
between thrombomodulin level and endothelial cells
impairment was analyzed by using Spearman’s Rho
test, and the result was rs ZLWK3
This study also found significant positive
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thrombomodulin level in detecting endothelial cells
disruption.
Endothelial cells have an important role in
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LQ '+) VXJJHVWV WKDW WKHUH LV LPSDLUPHQW LQ
integrity of the endothelial cells. This component
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maintaining homeostasis. Endothelial cells have
many receptors, besides producing vasoactive
products such as prostacyclin, platelet activating
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surveillance, prevention and control of dengue hemorrhagic
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release vasoactive agents.
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cells impairment with poor result. Therefore,
thrombomodulin level can be considered as an early
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patients. Furthermore, future research on vascular
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patient is needed.
References
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Firmansyah A, Sastroasmoro S, Trihono PT, editors. Abstract
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262‡Paediatr Indones, Vol. 49, No. 5, September 2009
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immunoassay for detection of dengue virus NS1 antigen in
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samples as a new approach for diagnosis of dengue virus
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Paediatr Indones, Vol. 49, No. 5, September 2009‡263