-
Hindawi Publishing CorporationISRN Infectious DiseasesVolume
2013, Article ID 571646, 6
pageshttp://dx.doi.org/10.5402/2013/571646
Review ArticlePathogenesis of Dengue Haemorrhagic Fever and Its
Impact onCaseManagement
Kolitha H. Sellahewa
Department of Medicine, Melaka Manipal Medical College, Jalan
Batu Hampar, Bukit Baru, 75150 Melaka, Malaysia
Correspondence should be addressed to Kolitha H. Sellahewa;
[email protected]
Received 5 September 2012; Accepted 30 September 2012
Academic Editors: R. Bologna, R. Favory, and K.
Sawanyawisuth
Copyright 2013 Kolitha H. Sellahewa. is is an open access
article distributed under the Creative Commons AttributionLicense,
which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properlycited.
Plasma leakage and intrinsic coagulopathy are the pathological
hall marks in dengue haemorrhagic fever (DHF). Viral
virulence,infection enhancing antibodies, cytokines and chemical
mediators in the setting of intense immune activation are the key
playersimplicated in the pathogenesis of DHF; the exact nature of
which is yet to be fully understood.e pathophysiological changes
theattended clinical features of plasma leakage necessitate
recognition of changing physiological parameters for the early
recognitionof plasma leakage and appropriate uid therapy. On the
other hand, the changes in the haematological indices resulting
fromcoagulopathy can tempt the clinician to initiate other
modalities of therapy. A clearer understanding of the pathogenesis
ofDHF and the appreciation that both of these fundamental
pathological changes share common pathogenic mechanisms
wouldfacilitate the appropriateness of management decisions and the
early recognition of severe disease. us, thrombocytopaenia,reduced
brinogen, and prolonged partial thromboplastin time early in the
disease course connoted severe disease and attendedplasma leakage
rather than clinical bleeding. e detection of plasma cytokine prole
by a multiple bead immunoassay could alsocomplement clinical
parameters in predicting severe disease early in the disease
course. us, MIP- indicates good prognosiswhile IFN- portends severe
disease.
1. Introduction
Infection by any one of the four serotypes of dengue virus(DENV)
remains asymptomatic in the vast majority. Clinicalspectrum among
symptomatic infection ranges from undif-ferentiated fever (viral
syndrome), dengue fever (DF), anddengue haemorrhagic fever (DHF) to
the expanded denguesyndrome with isolated organopathy (unusual
manifesta-tions). DF can be without haemorrhage or have
unusualhaemorrhage,whileDHF can bewithout shock orwith shock,that
is, dengue shock syndrome [1].
e WHO criteria for the clinical diagnosis of DHFrequires the
presence of acute and continuous fever of2 to 7 days, haemorrhagic
manifestations associated withthrombocytopenia (100,000 cells/c.mm
or less) and haemo-concentration (haematocrit >20% from baseline
of patientor population of same age). Haemorrhagic
manifestationscould be mucosal and or skin or even a positive
tourniquettest which is the commonest. Hepatomegaly occurs at
some
stage of DHF and oen precedes plasma leakage and hence avaluable
early predictor of plasma leakage [1].
DHF is most commonly seen in children with secondarydengue
infection but has been documented in primaryinfection with DENV-1
and DENV-3, as well as in infants.ese infants had acquired maternal
dengue antibody andsubsequently experienced a dengue infection [2].
Greaterbaseline vascular permeability among children could also bea
contributor for more severe disease among children thanamong adults
[3]. Epidemiological and serological studiesdone both in ailand and
Cuba support the importance ofsecondary dengue infections as a risk
factor for DHF. Sincethe rst observations by Halstead et al. in
170, DHF hasbeen present in situations where more than one
serotypecirculates [4, 5]. e disease burden and a resurgence
ofrecurrent epidemics of DHF are attributable to social dynam-ics
and a variety of epidemiological factors such as a highvector
density, a high virus circulation, and a population atrisk of
secondary infection by virtue of previous exposure
-
2 ISRN Infectious Diseases
[6]. Besides secondary infection, chronic diseases such
asbronchial asthma and diabetes have been suggested as riskfactors
for DHF. Also, whites have higher risk of developingDHF than
blacks. DENV-2 virus is known to replicate tohigher concentration
in the peripheral blood cells of whitescompared with those of
blacks [6].
Abnormal haemostasis and plasma leakage are the
mainpathophysiological hall marks in DHF. Even though morethan half
a century has elapsed since plasma leakage was rstidentied its
precise mechanism remains elusive. e mainfactor implicated in the
development of DHF rather thanthe relatively innocuous DF in dengue
infection is secondarydengue infection but other factors like viral
virulence andhost characteristics are also important. Severe
disease isthe result of a complex interaction between the virus
andthe immune response evoked by the host with secondaryinfection
[7].
2. Plasma Leakage in DHF
2.1. Pathophysiology. Plasma leakage is specic to the pleuraland
peritoneal surfaces. In DHF there is no vasculitis andhence no
injury to the vessel walls, and plasma leakage resultsfrom cytokine
mediated increase in vascular permeability.e ensuing movement of
albumin and the resultant reduc-tion of intravascular oncotic
pressure facilitate further loss ofuid from the intravascular
compartment. e basic Starlingprinciple still holds true in
explaining microvascular ultral-tration based on the balance of the
oncotic and hydrostaticpressures. However the glycocalyx, which is
a gelatinouslayer lining the vascular endothelium is also
implicated incontrolling uid movement by the adherence of
albuminmolecules in to its matrix, damage of which, leads to loss
ofalbumin into the extravascular compartment [811].
2.2. Immunopathogenesis. e immune system is implicatedin the
pathogenesis ofDHFowing to the increased propensityto develop DHF
with secondary dengue infection.e innateimmune mechanisms
comprising the complement pathwayand NK cells as well as humoral
and cell-mediated immunemechanisms launched in response to
antigenic stimulationare involved in the clinical manifestations.
Complementactivation as well as vascular permeability may be
inuencedby viral products like NS1. Different immune mechanisms
inthe form of antibody enhanced viral replication leading to
anexaggerated cytokine response impacts vascular
permeability[1214].
Infection with one dengue serotype elicits immunity tothat
serotype but does not provide long-term cross-protectiveimmunity to
the remaining serotypes. Subsequent infectionwith a different
serotype results in the binding of the newvirus to cross reactive
nonneutralising antibody from theprevious infection facilitating
the uptake by mononuclearphagocytes enabling amplied viral
replication.e resultingincrease in viral load then drives an
immunopathogeniccascade and the resultant exaggerated cytokine
response leadsto a transient increase in microvascularpermeability.
eprecise way in which microvascular permeability is alteredis not
clear but is more likely to be a functional change
rather than structural damage, as dengue shock is
rapidlyrecoverable, and no inammation is evident in the
leakingsurfaces [1519]. Adding to the complexity of the under-lying
immunopathogenic mechanisms resulting in changesin vascular
permeability is the proposal of an alternativemechanismwhereby the
rapidmobilisation of serotype cross-reactivememory T cells trigger
the release of biologicalmedi-ators. Some of the other factors
implicated in this orchestra-tion include viral virulence,
molecularmimicry, and immunecomplex and/or complement mediated
dysregulation, andgenetic predisposition, all of which have been
shown to corre-late with disease severity. However, as yet no
mechanism hasbeen identied that links any of these established
immuno-logical derangements with a denitive effect on
microvascu-lar structure or function consistent with the observed
alter-ation in permeability. In addition, most of the
immunologicalabnormalities so far identied do not differ
substantially fromthose seen in other infections without an
apparent effect onpermeability.
Neutralising antibodies are key factors in the
aetiopatho-genesis of the disease. However, the cellular
immuneresponse is also important. It has been demonstrated
thatmemory dengue T lymphocyte response aer a primaryinfection
includes both serotype-specic and serotype-cross-reactive T
lymphocytes [20]. NS3 protein seems to be themajor target for CD4+
and CD8+ T cells.
Cytokines that may induce plasma leakage such as inter-feron g,
interleukin (IL) 2, and tumour necrosis factor (TNF) are increased
in DHF cases [20, 21]. Also, interferon enhances uptake of dengue
particles by target cells throughincreasing Fc cell receptors
[22].Other cytokines such as IL-6,IL-8, and IL-10 are also
increased. A protein of 2225 kDa hasbeen associated with the
pathogenesis of DHF.is cytotoxicfactor able to induce increased
capillary permeability in miceis capable of reproducing in mice all
the pathological lesionsthat are seen in human beings, and has been
detected in seraof DHF patients [23].
A recent study has demonstrated the plasma cytokineprole in
dengue fever from a Brailian population whichwas detected by a
multiplex bead immunoassay. MIP-was indicated as a good prognostic
marker which is incontrast to IFN- that was associated with severe
disease.Both cytokines serve to discriminate mild from severe
cases.It has also been shown that during the course of
denguedifferent cytokine proles may be present and vary accordingto
determined clinical manifestations. e cytokine prolesidentied by
bead arraymultiplex systemmay favour an earlyidentication of
patients with the worst prognosis and maycontribute to the
establishment of more directed therapeuticprocedures than the
present ones [24].
Complement activation as a result of immune com-plexes
(virus-antibody) or immune activation and cytokineproduction could
also be involved in the mechanism ofplasma leakage. Certain
complement fragments such as C3aand C5a are known to enhance
permeability. NS1 antigenin dengue virus has been shown to regulate
complementactivation and hence could play a role in the
pathogenesisof DHF [12, 13, 2527]. Clearly immunopathogenic
mech-anisms are involved in plasma leakage and coagulopathy.
-
ISRN Infectious Diseases 3
However alternate immune pathways are also implicated in
aprotective role adding to the complexity and intricacy of
thepathogenesis of DHF. Activated NK cells release granzyme A,which
has cytolytic functions. MIP-1 produced by humanmonocytes and
dendritic cells as well as activated NK cellsand lymphocytes is
chemoattractant for NK cells, recruitingthem to inammatory sites.
ese mechanisms could play aprotective role in the immunopathology
of DHF by the earlyand efficient clearance of DENV by direct or
indirect NKfunctions thereby limiting viral replication and its
attendedcascading cytokine mediated plasma leakage. NK cells
havebeen associated with mild dengue [28, 29].
In summarymonocytes,macrophages, and dendritic cellsare the
major targets for DENV.
During secondary infection with a different DENVserotype
cross-reactive nonneutralising antibodies bind toDENV and
facilitate uptake via Fc receptors resulting inenhanced viral
replication. e resultant higher viral antigenload leads to an
exaggerated activation of cross-reactivedengue specic T cells.
iological mediators released bythe activated T cells as well as
virus infected cells alongwith complement activation by viral
proteins, and immunecomplexes are implicated in increasing vascular
permeabilityand coagulopathy.
ese biological mediators inuence clinical outcomesto a variable
extent. us IL-1, IFN-, IL-4, IL-6, IL-13, IL-7, and GM-CSF are
associated with severe clinicalmanifestations whileMIP-1 is
elevated in patients withmilddengue. Marked thrombocytopaenia is
evident in patientswith elevated IL-1, IL-8, TNF-, andMIP-1, while
increasedlevels of MIP-1 and GM-CSF correlated with
hypotension[24].
2.3. Haemorrhagic Manifestations in DHF. e pathogenesisof
bleeding in DHF is unclear even though well-recognisedcoagulation
disturbances do exist. e clinical haemorrhagicmanifestations range
from a mere positive tourniquet test,skin petechiae and ecchymoses
to epistaxis, and gumbleedingto severe gastrointestinal
haemorrhages.rombocytopaeniais a consistent nding, while prolonged
partial thrombo-plastin time and reduced brinogen concentration are
theother abnormal haemostatic indices evident from early in
thedisease course. ese haematological abnormalities seem
tocorrelate betterwith the timing and severity of plasma
leakagerather than the clinical haemorrhagic manifestations
[30].
ese recent ndings raise the possibility for commonpathogenic
mechanisms responsible for both plasma leakageand abnormalities in
the haemostatic indices.e true natureof the intrinsic coagulopathy
evident early in the diseasecourse and in mild forms of dengue can
be confounded bythe advent of hypovolemic shock and hypoxia in DHF
withsevere plasma leakage with less than optimal correction.
rombocytopaenia is initially due to bone marrowsuppression
during the febrile viraemic phase of the illness.Progressive
thrombocytopaenia with defervescence resultfrom immune mediated
platelet destruction. Virus-antibodycomplexes have been detected on
the platelet surface of DHFpatients suggesting a role for
immune-mediated destruction
of platelets [31, 32]. Augmented platelet adhesiveness
tovascular endothelial cells resulting from the release of
highlevels of platelet-activating factor by monocytes with
het-erologous secondary infection also contributes to the
throm-bocytopaenia [33]. rombocytopaenia however correlatespoorly
with bleeding manifestations. Spontaneous bleedingbeen uncommon
evenwith counts below 100,000 cells/c.mm.It is strongly associated
with the severity of vascular leakage.Counts below 100,000
cells/c.mm or a rapid drop in theplatelet count was associated with
severe disease.
e role of the glycocalyx rather than the endothelial cellsper se
in controlling ultraltration in the microvasculatureis increasingly
recognised and in vivo animal studies haveshown the permeation of
brinogen to the endothelial surfacesimilar to albumin [11].
e low plasma brinogen detected in DHF could thusbe a reection of
loss into the interstitial spaces in the settingof increased
vascular permeability. Heparan sulphate formsan integral part of
the glycocalyx which when damaged bythe initial cytokine response
in DHF gets liberated to thecirculation and acts like an
anticoagulantwhich could explainthe prolonged APTT [34]. e
disturbance in both theseimportant haemostatic indices are unlikely
to cause sponta-neous bleeding.Haemorrhages are triggered by trauma
in thissetting of coagulopathy.
Development of antibodies potentially cross-reactive
toplasminogen could have a role in causing haemorrhage inDHF [35].
However different studies have shown conictingresults as some have
demonstrated an activation of brinol-ysis while others have shown
an inhibition of the brinolyticpathway in DHF [30].
2.4. Endothelial Cells in DHF. Precise knowledge on theextent to
which DENV infects endothelial cells is lacking asfew studies have
addressed the issue in the viraemic phase ofthe illness. Even
though DENV has infected endothelial cellsin vitro it is doubtful
whether it reects the effect in humaninfection as limited human
autopsy studies have detectedonly the dengue antigen but not the
genome in various celltypes ranging frommonocytes, liver sinusoidal
cells, alveolarmacrophages, peripheral blood, and splenic
lymphocytes.How important these ndings are in the pathogenesis
ofclinical features are uncertain as some studies have
shownswelling of endothelial cells but not cell death or
vasculitis[36], while others have detected apoptosis of endothelial
cellsin lungs and intestinal mucosa in fatal DHF cases, but
theextent of apoptosis has not been documented [36]. DENValters the
endothelial cell surface protein production, itsexpression, and
transcriptional activity.
Expression of ICAM-1 (intercellular adhesion molecule-1) and
beta-integrin on micro vascular endothelium byDENV has been
reported. DENV also affects the expressionof cytokine receptors.
ese may contribute to the mecha-nisms involved in plasma leakage in
DHF.
e role of DENV infected endothelial cells in thepathogenesis of
coagulopathy in DHF is equally intriguing.ere is upregulation of
tissue plasminogen, thrombomod-ulin, protease activated receptor-1,
and tissue factor receptor,
-
4 ISRN Infectious Diseases
while there is downregulation of tissue factor inhibitor
andactivated protein C.
3. Clinical Implications
DHF cases have increased in the recent past andwill continueto
increase in numbers in time to come as DHF is commonerin secondary
dengue infection. e probability of secondarydengue infection in a
given population is expected to increaseowing to the presumed high
prevalence of previous exposureto clinical or asymptomatic dengue
infection based on epi-demiological data particularly in dengue
endemic regions inthe world. Despite the complexity of the
immunopathogenicmechanism involved in severe disease, what is
inexorableis that all patients with DHF have plasma leakage,
themagnitude and progression of which will impact outcome.Dengue
infection must be diagnosed early and in all suchpatients
clinicians need to be alert and vigilant to identifyDHF patients
early at the inception of plasma leakage beforeshock sets in.
Appropriate interventions with udicious uidtherapy at this stage
could offset adverse outcomes andensure a favourable outcome.
Immunopathogenic mecha-nisms implicated in DHF could serve to meet
the challengesof identifying in the febrile phase patients who
could behaveas DHF during the disease course. In this context assay
ofspecic biomarkers identied in dengue could be useful.uswhile
MIP-1 indicates good prognosis, IFN- portendssevere disease.
Clinicians should also appreciate that bothplasma leakage and
disturbances of haemostatic indices sharecommon immunopathogenic
mechanisms. Disturbances inthe haemostatic indices should thus be
correlated to theseverity of plasma leakage rather than the
tendency forspontaneous clinical bleeding manifestations. Such
consid-erations would serve to complement the accuracy of
theprediction and identication of patients with severe
disease.Intelligent application of such knowledge in relation to
thetemporal relation of the disease course will also
facilitateinterventional decisionmaking and improve its accuracy
andappropriateness. us, low plasma brinogen and prolongedAPTT in
the absence of shock early in the disease is to beexpected inDHF
and interpreted as heralding plasma leakageand not DIC, and its
magnitude gives an idea of the severityof leakage. On the contrary
the same indices of coagulopathyshould have a different
interpretation in the setting of shockowing to the confounding
effects of hypovolemia and hypoxiaand even the probability of
associated DIC in such a setting.
Similarly thrombocytopaenia is best used as a markerof severe
disease particularly when it is
-
ISRN Infectious Diseases 5
therapeutic interventions. Use of fresh frozen plasma for
thispurpose is an exciting area of research [37].
References
[1] WHO, Comprehensive Guidelines for Prevention and Control
ofDengue and Dengue Haemorrhagic Fever, 2011.
[2] S. C. Kliks, S. Nimmanitya, A. Nisalak, and D. S.
Burke,Evidence thatmaternal dengue antibodies are important in
thedevelopment of dengue hemorrhagic fever in
infants,AmericanJournal of Tropical Medicine and Hygiene, vol. 38,
no. 2, pp.411419, 1988.
[3] J. Gamble, D. Bethell, N. P. J. Day et al., Age-related
changes inmicrovascular permeability: a signicant factor in the
suscepti-bility of children to shock? Clinical Science, vol. 98,
no. 2, pp.211216, 2000.
[4] N. Sangkawibha, S. Rojanasuphot, and S. Ahandrik,
Riskfactors in dengue shock syndrome: a prospective
epidemiologicstudy in Rayong, ailand. I. e 1980 outbreak,
AmericanJournal of Epidemiology, vol. 120, no. 5, pp. 653669,
1984.
[5] M. G. Guzman, G. P. Kouri, J. Bravo, M. Soler, S.
Vazquez,and L. Morier, Dengue hemorrhagic fever in Cuba, 1981:a
retrospective seroepidemiologic study, American Journal
ofTropicalMedicine andHygiene, vol. 42, no. 2, pp. 179184,
1990.
[6] G. P. Kouri, M. G. Guzmn, and J. R. Bravo, Why
denguehaemorrhagic fever in Cuba? 2. An integral analysis,
Transac-tions of the Royal Society of Tropical Medicine and
Hygiene, vol.81, no. 5, pp. 821823, 1987.
[7] M.G.Guzmn,G.Kouri, L. Valdes et al., Epidemiologic studieson
dengue in Santiago de Cuba, 1997, American Journal ofEpidemiology,
vol. 152, no. 9, pp. 793799, 2000.
[8] B. A.Wills, N. M. Dung, H. T. Loan et al., Comparison of
threeuid solutions for resuscitation in dengue shock syndrome,eNew
England Journal of Medicine, vol. 353, no. 9, pp. 877889,2005.
[9] C. C. Michel and F. E. Curry, Microvascular
permeability,Physiological Reviews, vol. 79, no. 3, pp. 703761,
1999.
[10] V. H. Huxley and F. E. Curry, Differential actions of
albuminand plasma on capillary solute permeability, American
Journalof Physiology, vol. 260, no. 5, pp. H1645H1654, 1991.
[11] B. A. Wills, E. E. Oragui, M. D. Nguyen et al., Size and
chargecharacteristics of the protein leak in dengue shock
syndrome,Journal of Infectious Diseases, vol. 190, no. 4, pp.
810818, 2004.
[12] P. Avirutnan,N. Punyadee, S. Noisakran et al., Vascular
leakagein severe dengue virus infections: a potential role for
thenonstructural viral protein NS1 and complement, Journal
ofInfectious Diseases, vol. 193, no. 8, pp. 10781088, 2006.
[13] P. Avirutnan, A. Fuchs, R. E. Hauhart et al., Antagonism of
thecomplement component C4 by avivirus nonstructural proteinNS1,e
Journal of Experimental Medicine, vol. 207, no. 4, pp.793806,
2010.
[14] P. Avirutnan, L. Zhang, N. Punyadee et al., Secreted NS1
ofdengue virus attaches to the surface of cells via interactions
withheparan sulfate and chondroitin sulfate E, PLoS Pathogens,
vol.3, no. 11, article e183, 2007.
[15] S. Halstead, Pathophysiology and pathogenesis of
denguehemorrhagic fever, in Monograph on Dengue/Dengue
Haem-orrhagic Fever, P. ongcharoen, Ed., Regional Publication,SEARO
no. 22, pp. 80103, WHO, 1993.
[16] D. M. Morens, Antibody-dependent enhancement of
infectionand the pathogenesis of viral disease, Clinical Infectious
Dis-eases, vol. 19, no. 3, pp. 500512, 1994.
[17] S. C. Kliks, A. Nisalak, W. E. Brandt, L. Wahl, and D. S.
Burke,Antibody-dependent enhancement of dengue virus growth inhuman
monocytes as a risk factor for dengue hemorrhagicfever, American
Journal of Tropical Medicine and Hygiene, vol.40, no. 4, pp.
444451, 1989.
[18] D.W. Vaughn, S. Green, S. Kalayanarooj et al., Dengue
viremiatiter, antibody response pattern, and virus serotype
correlatewith disease severity, Journal of Infectious Diseases,
vol. 181, no.1, pp. 29, 2000.
[19] D. H. Libraty, T. P. Endy, H. S. H. Houng et al.,
Differinginuences of virus burden and immune activation on
diseaseseverity in secondary dengue-3 virus infections, Journal
ofInfectious Diseases, vol. 185, no. 9, pp. 12131221, 2002.
[20] I. Kurane and F. A. Ennis, Cytokines in dengue virus
infec-tions: role of cytokines in the pathogenesis of dengue
hemor-rhagic fever, Seminars in Virology, vol. 5, no. 6, pp.
443448,1994.
[21] S. Green, S. Pichyangkul, D. W. Vaughn et al., Early
CD69expression on peripheral blood lymphocytes
fromchildrenwithdengue hemorrhagic fever, Journal of Infectious
Diseases, vol.180, no. 5, pp. 14291435, 1999.
[22] U. Kontny, I. Kurane, and F. A. Ennis, Gamma
interferonaugments Fc() receptor-mediated dengue virus infection
ofhuman monocytic cells, Journal of Virology, vol. 62, no. 11,
pp.39283933, 1988.
[23] R. Mukerjee, U. C. Chaturvedi, and R. Dhawan, Dengue
virus-induced human cytotoxic factor: production by peripheralblood
leucocytes in vitro, Clinical and Experimental Immunol-ogy, vol.
102, no. 2, pp. 262267, 1995.
[24] F. A. Bozza, O. G. Cruz, S. M. O. Zagne et al.,
Multiplexcytokine prole from dengue patients: MIP-1beta and
IFN-gamma as predictive factors for severity, BMC
InfectiousDiseases, vol. 8, article 86, 2008.
[25] I. Kurane and T. Takasaki, Dengue fever and dengue
haemor-rhagic fever: challenges of controlling an enemy still at
large,Reviews in Medical Virology, vol. 11, no. 5, pp. 301311,
2001.
[26] C. L. Medin, K. A. Fitzgerald, and A. L. Rothman,
Denguevirus nonstructural protein NS5 induces interleukin-8
tran-scription and secretion, Journal of Virology, vol. 79, no. 17,
pp.1105311061, 2005.
[27] P. Avirutnan, E. Mehlhop, and M. S. Diamond, Complementand
its role in protection and pathogenesis of avivirus infec-tions,
Vaccine, vol. 26, no. 8, pp. I100I107, 2008.
[28] E. L. Azeredo, L. M. De Oliveira-Pinto, S. M. Zagne, D.
I.S. Cerqueira, R. M. R. Nogueira, and C. F. Kubelka, NKcells,
displaying early activation, cytotoxicity and adhesionmolecules,
are associated with mild dengue disease, Clinicaland Experimental
Immunology, vol. 143, no. 2, pp. 345356,2006.
[29] B. G. Dorner, H. R. C. Smith, A. R. French et al.,
Coordinateexpression of cytokines and chemokines by NK cells
duringmurine cytomegalovirus infection,e Journal of Immunology,vol.
172, no. 5, pp. 31193131, 2004.
[30] B. Wills, V. N. Tran, N. T. H. Van et al., Hemostatic
changesin Vietnamese children with mild dengue correlate with
theseverity of vascular leakage rather than bleeding,
AmericanJournal of Tropical Medicine and Hygiene, vol. 81, no. 4,
pp.638644, 2009.
[31] S. Wang, R. He, J. Patarapotikul, B. L. Innis, and R.
Anderson,Antibody-enhanced binding of dengue-2 virus to
humanplatelets, Virology, vol. 213, no. 1, pp. 254257, 1995.
-
6 ISRN Infectious Diseases
[32] C.-F. Lin, H.-Y. Lei, C.-C. Liu et al., Generation of IgM
anti-platelet autoantibody in dengue patients, Journal of
MedicalVirology, vol. 63, no. 2, pp. 143149, 2001.
[33] K. D. Yang, C. L. Wang, and M. F. Shaio, Production
ofcytokines and platelet activating factor in secondary denguevirus
infections, Journal of Infectious Diseases, vol. 172, no. 2,pp.
604605, 1995.
[34] R. N. Palmer, M. E. Rick, and P. D. Rick, Circulating
heparansulfate anticoagulant in a patient with fatal bleeding
disorder,e New England Journal of Medicine, vol. 310, no. 26,
pp.16961699, 1984.
[35] E. Chungue, L. Poli, C. Roche, P. Gestas, P. Glaziou, and
L. J.Markoff, Correlation between detection of plasminogen
cross-reactive antibodies and hemorrhage in dengue virus
infection,Journal of Infectious Diseases, vol. 170, no. 5, pp.
13041307,1994.
[36] A. Srikiatkhachorn, Plasma leakage in dengue
haemorrhagicfever, rombosis and Haemostasis, vol. 102, no. 6,
pp.10421049, 2009.
[37] K. H. Sellahewa, A hypothetical intervention to reduce
plasmaleakage in dengue haemorrhagic fever,WHO Dengue Bulletin,vol.
35, pp. 9498, 2011.
-
Submit your manuscripts athttp://www.hindawi.com
Stem CellsInternational
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
Disease Markers
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation
http://www.hindawi.com Volume 2014
Immunology ResearchHindawi Publishing
Corporationhttp://www.hindawi.com Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttp://www.hindawi.com Volume
2014
Parkinsons Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing
Corporationhttp://www.hindawi.com