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A molecular mimicryoccurs between platelets/endothelial cells and dengue virus antigens. Platelets andendothelial cells arebound by the cross-reactive anti-dengue virus antibodies such as anti-NS1 or anti-prMantibodies

It is characteried bybiphasic !ever" myalgia" headache" pain in various partso! the body" rash" lymphadenopathy" and leucopenia

Not all #$%/#SS cases are secondary in!ections.Although most o! the #$%/#SS in children aresecondary in!ection" but the #$%/#SS in in!ants areprimary in!ection. &omplement activation may be theresult o! severe disease" not the cause o! #$%/#SS.

#$% develops rapidly" usually over a period o! hours"and resolves within 1 to ' days in patients who receive

appropriate (uid resuscitation.

Pato)siologi#engue virus in!ection causes aberrant immuneresponses. *hese aberrant immune responses not onlyimpair the immune response to clear the virus" result inoverproduction o! cyto+ines" as well as abnormalproduction o! autoantibodies. *he aberrant generationo! anti-NS1 antibodies that cross-react with platelet orendothelial cells initiates the subse,uent developmento! dengue disease. Anti-platelet or anti-endothelial cellautoantibodies must be involved in the clinicalmani!estation o! thrombocytopenia and endothelial celldys!unction. #engue virus in!ection-caused endothelialdamage and bleeding also contribute to the hemorrhage"and the imbalance between coagulation and )brinolysisactivation increases the li+elihood o! severehemorrhage in #$%/#SS. $emostasis is maintainedunless the dysregulation o! coagulation and )brinolysispersists.

ImmunopathogenesisImmunopathogenesis in dengue hemorrhagic !everhas been proposed1"10. Serotype cross-reactive

antibodies !rom the previous in!ection bind to virionswithout neutraliation and enhance the entry o! virusinto monocytes. *he number o! virus-in!ectedmonocytes increases. As a result" the level o! denguevirus-speci)c * cell activation is mar+edly enhanced.*he * cells" especially the cross-reactive * cells"produce cyto+ines such as I%N-g" I-' and *N%a andlyse dengue virus-in!ected monocytes. *N%a is alsoproduced by activated monocytes. *he complementcascade is activated by a virus-antibody comple2 aswell as by several cyto+ines to release &3a and &awhich also have direct e4ects on vascular permeability.*he synergistic e4ects o! I%N-g" *N%a and activated

complement proteins trigger plasma lea+age o!endothelial cells in secondary dengue virus in!ection.

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#engue !everis an acute !ebrile illnesswith headache" retro-orbital pain" myalgia" arthralgia"rash" leu+openia and mild thrombocytopenia. 5iphasic

!ever 6!ever then no !ever !or !ew days then again !ever7and rash are the most characteristic !eatures o!classic dengue !ever. Symptoms resolve a!ter ' to8 days.

#engue hemorrhagic !everis an acute vascularpermeability syndrome accompanied by abnormalitiesin hemostasis. *he clinical !eatures include plasmalea+age" bleeding tendency" and liver involvement1"'0.&apillary lea+age develops rapidly over a period o!hours" near or at the end o! the !ebrile period when the

symptoms o! classic #% resolve. Pleural e4usion"ascites" and hemoconcentration are indicative o!intravascular volume loss. It can ,uic+ly progress toshoc+ i! patients do not receive intravascular (uidresuscitation. *he hemorrhagic mani!estations range !rom a positive tourni,uet test tospontaneous bleeding!rom the nose or the gastrointestinal tract.$emoconcentration and mar+ed thrombocytopenia aretwo ma9or characteristic !eatures o! #$%/#SS. iverinvolvement is common in dengue virus in!ectionwith mild elevation o! serum transaminases.

Ample

studies demonstrate that dengue virus can in!ect avariety o! human primary cells includingmonocytes/macrophages" dendritic cells" 5 cells"hepatocytes" :up4er cells and cell lines o! endothelialand epithelial origin. $owever" these in vitro in!ectionsare modulated by the cell type and viral strain1;0.*here!ore" damage or dys!unction o! these cells ororgans induced by dengue virus in!ection" eitherdirectly or indirectly is responsible !or the progressivedevelopment o! #$%/#SS.

anti-platelet and antiendothelialcell IgM or IgAN*?S

1. @e have reported that the anti-NS1 antibodies cancross-react with non-in!ected endothelial cells andinduce these cells to undergo apoptosis7

'. #engue virus-in!ected endothelial cells are capableo! activating complement and inducing the e2pressiono! adhesion molecules such as I&AM-10. *hee2pression o! I&AM-1 together with the production o!chemo+ines I-; and >AN*?S increases the adherenceo! polymorphonuclear cells and mononuclear cells"respectively" and results in increased vasopermeability

and thrombomodulin 6is anintegral membrane proteinexpressed on the

surface of endothelial cells -- induced activation ofprotein Cin theanticoagulantpathway by forming a 1:1 stoichiometric complex with

thrombin.7 release" a mar+er o! endothelialcell damage.

It seems that both direct viral cytopathice4ects and immune mediated damage by leu+ocyterecruitment can cause structural in9ury to in!ectedendothelial cells

*his vascular lea+age can be inducedeither directly or indirectly during dengue virusin!ection.

http://en.wikipedia.org/wiki/Integral_membrane_proteinhttp://en.wikipedia.org/wiki/Protein_Chttp://en.wikipedia.org/wiki/Anticoagulanthttp://en.wikipedia.org/wiki/Protein_Chttp://en.wikipedia.org/wiki/Anticoagulanthttp://en.wikipedia.org/wiki/Integral_membrane_protein

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Moreover" although the endothelial cellsur!ace molecules that are recognied by theseautoreactive antibodies need to be identi)ed" a crossreactivitye2ists between endothelial cells and denguevirus antigens due to the molecular mimicry.*he

endothelial cells do not need to be in!ected by denguevirus to be targeted. *he cross-reactive anti-dengueantibody such as anti-NS1 or anti-prM can bind to theun-in!ected endothelial cells to cause its damage.

5ecause endothelium plays a crucial role in maintaininghemostasis" damage o! endothelial cells during denguevirus in!ection may s+ew the procoagulant/anticoagulant balance o! endothelium and increase thebleeding tendency.

*he se,uestration o! platelets byactivated endothelial cells might also contribute to the

development o! thrombocytopenia.

&oagulopathy#uring acute dengue virus in!ection" coagulationparameters such as platelet counts" activated partialthromboplastin time 6AP**7 as well as )brinolyticparameters o! tPA and PAI-1 are altered. AP** isprolonged while tPA increases. 5oth coagulation and)brinolysis are activated" and this activation is muchmore severe in #$%/#SS than in #% patients. A!terconvalescence" rises in the PAI-1 level and plateletcounts are concomitant with the decline in the tPA leveland a return to normal o! AP**. *he tPA/PAI-1 ratio ishigher in #$%/#SS than in #% patients. AP**prolongation and tPA/PAI-1 ratio increase in the acutestage o! dengue virus in!ection correlate with diseaseseverity and can be used as early indicators o!#$%/#SS8

AP**prolongation and tPA/PAI-1 ratio increase in the acutestage o! dengue virus in!ection correlate with diseaseseverity and can be used as early indicators o!

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