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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. 'HQJXH KHPRUUKDJLF IHYHU '+)  KDV VHYHUDO
Thrombomodulin is a part of glycoprotein membrane in clinical features such as fever, rash, hemorrhage,
endothelial cells. Therefore, thrombomodulin level will
liver enlargement, ascites, and encephalopathy.
increase if endothelial cells disruption occurs.
Objective 7R DFNQRZOHGJH WKH FRUUHODWLRQ EHWZHHQ WKH '+) JUDGH ,,, DQG ,9 DUH WKH VHYHUH PDQLIHVWDWLRQ
degree of dengue hemorrhagic fever and thrombomodulin of this disease. Until now, there are several theories
level. UHJDUGLQJWKHSDWKRJHQHVLVRI'+)LHYLUDOYLUXOHQFH
Methods 7KLVZDVDFURVVVHFWLRQDOVWXG\6XEMHFWVZHUH LPPXQRSDWKRORJ\ DQWLJHQDQWLERG\ FRPSOH[
hospitalized pediatric patients with age ranging from one endothelial cells and thrombocyte, also apoptosis.
WR\HDUROGLQSHGLDWULFZDUGDW3URI'U5'.DQGRX
Thrombocyte and endothelial cells are predicted
+RVSLWDO0DQDGRZKRKDGIHYHU7KUHHPLOOLOLWHUVRIEORRG
ZHUHWDNHQIURPYHLQDQGZHUHGLYLGHGIRUWZRWHVWVZKLFK WR KDYH DQ LPSRUWDQW UROH LQ '+) SDWKRJHQHVLV
were routine blood analysis and thrombomodulin analysis. Manifestations such as thrombocytopenia and
'LIIHUHQWGDWDUHVXOWHGIURPWKHGHQJXHKHPRUUKDJLFIHYHU LQFUHDVLQJFDSLOODU\SHUPHDELOLW\LQ'+)VXJJHVWWKDW
group were processed, and analyzed statistically using F Test there is impairment in integrity of endothelial cells.
DQG /6' OHDVW VLJQLILFDQW GLIIHUHQFH  WHVW 7KH UHODWLRQ 7KHVHWZRFRPSRQHQWVKDYHEHHQNQRZQDVKDYLQJ
between dengue hemorrhagic fever and thrombomodulin
united function in maintaining homeostasis. If one of
was analyzed with Spearman correlation coefficient.
Results There was a significant result in the difference of the components is damaged, it will affect the other.
thrombomodulin level on four dengue hemorrhagic fever Thrombocyte has another function as secretory cell
groups which were classified according to the severity of which has granules containing various mediators.
dengue hemorrhagic fever. There was a very significant Endothelial cells have numerous receptors, besides
positive correlation between the severity of dengue producing vasoactive products such as prostacyclin,
hemorrhagic fever and thrombomodulin level in detecting
endothelial cells impairment.
Conclusion Thrombomodulin level can be used as a
PDUNHUWRGHWHFWHQGRWKHOLDOFHOOVLPSDLUPHQWLQGHQJXH )URPWKH'HSDUWPHQWRI&KLOG+HDOWK0HGLFDO6FKRRO6DP5DWXODQJL
KHPRUUKDJLF IHYHU +LJKHU JUDGH RI GHQJXH KHPRUUKDJLF 8QLYHUVLW\3URI5'.DQGRX*HQHUDO+RVSLWDO0DQDGR,QGRQHVLD
fever will have higher thrombomodulin level. [Paediatr
Indones. 2009;49:259-63]. Reprint request to:+HQGUD:LGMDMD0''HSDUWPHQWRI&KLOG+HDOWK
0HGLFDO6FKRRO6DP5DWXODQJL8QLYHUVLW\3URI5'.DQGRX*HQHUDO
+RVSLWDO-O5D\D7DQDZDQJNR0DQDGR,QGRQHVLD7HOS
Keywords: dengue hemorrhagic fever, thrombo-  )D[  (PDLO hw_230670@yahoo.co.id,
modulin, endothelial cells h3nw1@doctor.com

Paediatr Indones, Vol. 49, No. 5, September 2009‡259


Hendra Widjaja et al: (IIHFWRI'+)RQWKURPERPRGXOLQOHYHO

platelet activating factor 3$) SODVPLQRJHQIDFWRU 'HVFULSWLYH DQDO\VLV DQG 6SHDUPDQ·V 5KR FRUUHODWLRQ
LQWHUOHXNLQDQGWKURPERPRGXOLQ(QGRWKHOLDOFHOOV analysis were used in this research. All of the obtained data
disruption results in thrombocyte aggregation and ZHUHSURFHVVHGE\XVLQJ6366YHUVLRQ'DWDUHVXOWVKDG
activates coagulation. DFRQILGHQFHLQWHUYDO &, DQG3
Thrombomodulin concentration on endothelial
DFWLYDWLRQ LV UHODWHG WR VKRFN ZKLOH 3$, FRQFHQ
WUDWLRQ LV UHODWHG WR PDVVLYH EOHHGLQJ 'HQJXH YLUXV Results
will immediately activate primary pathogenesis, direct
GHJUDGDWLRQ RI ILEULQRJHQ RU VHFRQGDU\ SDWKRJHQHVLV 6XEMHFWV ZHUH  KRVSLWDOL]HG SDWLHQWV ZLWK '+)
by activating procoagulant hemostatis mechanism. FRQVLVWHGRIVXEMHFWVLQLQWHQVLYHFDUHURRP ,&8 
(QGRWKHOLDOSURWHLQ&UHFHSWRU (3&5 KDVDQLPSRUWDQW DQGVXEMHFWVLQSHGLDWULFZDUG Irina E 3URI'U
UROHLQFRQWUROOLQJWKHDFWLYLW\RI&SURWHLQ%\DGGLQJ 5' .DQGRX +RVSLWDO 0DQDGR )URP  VXEMHFWV
PRQRFORQDODQWLERG\LWZLOOEORFNWKH&SURWHLQELQGLQJ VXEMHFWVZHUHGLDJQRVHGZLWK'+)JUDGH,HLJKW
LQ(35ZKLFKZLOOUHVXOWLQKLJKHUULVNRIGHDWK ZLWK'+)JUDGH,,HLJKWZLWK'+)JUDGH,,,DQGVL[
ZLWK'+)JUDGH,92QGDLO\REVHUYDWLRQRQHSDWLHQW
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Methods ZLWK'+)JURXS,9GLHG
7KHORZHVWWKURPERPRGXOLQOHYHOZDVQJ
This research used analytical observation method POZKLOHWKHKLJKHVWZDVQJPO7KHPHDQYDOXH
ZLWK FURVVVHFWLRQDO DSSURDFK RQ DOO '+) FDVHV 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 HQGRWKHOLDOGLVUXSWLRQ+LJKHUVHYHULW\RI'+)UHVXOWHG
had fever. The data were obtained from anamnesis, in higher level of thrombomodulin. Thrombomodulin
physical examination, routine blood analysis, and level is being used as a probe to detect endothelial cells
thrombomodulin examination using ELISA method. disruption, which can be seen on Figure 1.
The inclusion criteria were children aged one The difference of thrombomodulin level in the
WR\HDUVROGZKRZHUHGLDJQRVHGZLWK'+)EDVHG IRXUJURXSV JUDGH,WR,9 KDGDVLJQLILFDQWGLIIHUHQFH
RQ  :+2 FULWHULD DQG ZKRVH SDUHQWV DJUHHG ZLWK)WHVW 3 DVVKRZQLQTable 2.
to participate in this study by filling the research The result of thrombomodulin level was used
form. Exclusion criteria were children with malaria, to detect endothelial cells disruption, as shown in
disseminated intravascular coagulation, diabetes Table 3.
PHOOLWXV.DZDVDNLGLVHDVHDFXWHJORPHUXORQHSKULWLV The correlation between thrombomodulin level
and systemic lupus erythematosus. DQGVHYHULW\RI'+)ZDVDQDO\]HGXVLQJ6SHDUPDQ·V
There were two types of variable in this research, Rho coefficient analysis. Based on this analysis, the
LHQRQGHSHQGHQWYDULDEOH WKHVHYHULW\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


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et al performed a study on thrombomodulin level by
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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 GLIIHUHQFH 3 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
YDOXHVKDGDVLJQLILFDQWGLIIHUHQFH 3 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. DVLJQLILFDQWGLIIHUHQFH 3 E\XVLQJ7WHVW
7KHFRPSDULVRQEHWZHHQ'+)JUDGH,,DQGJUDGH,9
ZDVDQGWKHUHZDVDOVRDVLJQLILFDQWGLIIHUHQFH
TM = 3.64 + 2.53 * D 3 E\XVLQJ7WHVW7KHFRPSDULVRQEHWZHHQ
20.00 Rs = 0.755 (p<0.001)
'+)JUDGH,,,ZLWKJUDGH,9ZDVDQGWKHUHZDV
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The level of thrombomodulin will rise on dengue
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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  6DPVL  7. 6XVDQWR , :XOXU + 5XVSDQGML 7 'LDJQRVH
between thrombomodulin level and endothelial cells RI GHQJXH KHPRUUKDJLF IHYHU SUREOHPDWLF &HUPLQ 'XQLD
impairment was analyzed by using Spearman’s Rho .HGRNWHUDQ
test, and the result was rs ZLWK3  :+2 *XLGHOLQHV IRU WUHDWPHQW GHQJXH IHYHUGHQJXH
This study also found significant positive KHPRUUKDJLFIHYHULQVPDOOKRVSLWDO*HQHYD:+2
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thrombomodulin level in detecting endothelial cells  :+2 7HFKQLFDO JXLGHOLQHV IRU GLDJQRVLV WUHDWPHQW
disruption. surveillance, prevention and control of dengue hemorrhagic
Endothelial cells have an important role in IHYHU *HQHYD $GYLVRU\ FRPPLWWHH RQ GHQJXH KHPRUUKDJLF
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integrity of the endothelial cells. This component IRUKHDOWKFDUHSUDFWLWLRQHUV6DQ-XDQ3XHUWR5LFR&'&
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maintaining homeostasis. Endothelial cells have  :+2 'HQJXH IHYHU LQ ,QGRQHVLD >KRPHSDJH RQ WKH
many receptors, besides producing vasoactive LQWHUQHW@F>XSGDWHG0DUFK@$YDLODEOHIURP
products such as prostacyclin, platelet activating http://www.who int/csr/don/2004-03-U5/en.
factor 3$) SODVPLQRJHQIDFWRULQWHUOHXNLQDQG  6XWDU\R 'HQJXH LQ <RJ\DNDUWD ,Q 0HGLND <RJ\DNDUWD
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release vasoactive agents.  'XVVDUW3/DEHDX%/DJDWKX*(YDOXDWLRQRIDQHQ]\PH
In conclusion, thrombomodulin level can be used immunoassay for detection of dengue virus NS1 antigen in
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WKURPERPRGXOLQOHYHO+LJKWKURPERPRGXOLQOHYHOLQ samples as a new approach for diagnosis of dengue virus
'+)JUDGH,9VXJJHVWVWKDWWKHUHLVYDVWHQGRWKHOLDO LQIHFWLRQ-&OLQ0LFURELRO
cells impairment with poor result. Therefore, 14. Franchini G, Ambinder RF, Barry M. Viral disease in
thrombomodulin level can be considered as an early KHPDWRORJ\+HPDWRORJ\
PDUNHUWRGHWHFWHQGRWKHOLDOFHOOVLPSDLUPHQWLQ'+)  /LQ &) &KLX 6& +VLDR </ ([SUHVVLRQ RI F\WRNLQH
patients. Furthermore, future research on vascular FKHPRNLQH DQG DGKHVLRQ PROHFXOHV GXULQJ HQGRWKHOLDO
HQGRWKHOLDOFHOOVUHODWHGWRRWKHUFRQGLWLRQLQ'+) cell activation induced by antibodies against dengue virus
patient is needed. QRQVWUXFWXUDOSURWHLQ-,PPXQRO
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human endothelial cells through binding of the viral envelope
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GLVHDVH-DNDUWD).8, conducive to permeability increase are induced by dengue
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RI.21,.$;,-DNDUWD,QGRQHVLDQ3HGLDWULF6RFLHW\ FHOOV-*HQ9LURO
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262‡Paediatr Indones, Vol. 49, No. 5, September 2009


Hendra Widjaja et al: (IIHFWRI'+)RQWKURPERPRGXOLQOHYHO

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localization. -'HY%LRO. normalities in dengue hemorrhagic fever serial investigations
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Paediatr Indones, Vol. 49, No. 5, September 2009‡263