pathophysiology of bleeding in dengue virus infection

1. PATHOPHYSIOLOGY OF BLEEDING
IN DENGUE VIRUS INFECTION
Dr Nandakanta Mahanta
PGT Pathology
MODERATOR:
Dr M.K . Deka
Asso Professor
Dr. R. Biswas
Assist Professor

2. INTRODUCTION
• Dengue virus is widely distributed throughout the tropic
and subtropics.
• Flavie virus
• Four types :
• DENV1 : Hawai in 1944
• DENV2 : New guinea in 1944
• DENV3 & 4 : Phillipines 1956

3. • Each serotype : specific lifetime immunity ; short time
cross immunity
• All serotypes can cause severe and fatal disease
• DENV2 :: most hemorrhagic

4. • Vector borne disease
• Aedes aegypti
mosquitoes

5. • asymptomatic viral infection to DHF /DSS
• Secondary dengue infection causing more severe
disease than primary dengue infection
• non neutralising heterologous abs: ADE

6. • HEMORRHAGE: high viral titre, macrophage
infiltration, TNF-α production in the local tissues
• DHF pathogenesis : T lymphocyte activation, production
of cytokines /chemokines, and complement activation

7. CLINICAL FEATURE
• FEBRILE PHASE:
• CRITICAL PHASE :
• RECOVERY PHASE

8. • DV affects : liver, vascular EC and platelets &
severe infection : DIC
• Liver dysfunction and abnormal coagulation: T
lymphocyte response to infected liver cells and cytokine
storm

9. • Hemorrhage in DV infection a result of
– viral characteristics ,
– humoral and cellular immune response of the host leading to
cytokine storm,
– direct effect of the virus on the bone marrow, platelet and
vascular endothelial cells

10. LABORATORY FINDINGS
• 1. CBC : thrombocytopenia , leukopenia
• 2. Mild to moderate elevation :: AST , ALT
• 3. ↑HCT
• 2. Serologic tests::
– antigen-detection ELISA (NS1 Ag)
– by IgM ELISA
– PCR during the acute phase of the disease

11. BLEEDING IN DF & DHF
• Thrombocytopenia & platelet dysfunction
• DIC & Hyperfibrinolysis
• Reduced synthesis of coagulation factors :: hepatitis
• In DHF : increased aPTT and PT
very low fibrinogen level and
reduced F VIII levels

12. Thrombocytopenia & platelet dysfunction

13. Two basic mechanism of thrombocytopenia :
• 1. reduced production of platelets
• 2. increased peripheral destruction of released platelets
– Immunological
– Non immunological destruction

14. PERIPHERAL ACTIVATION OF PLATELETS

15.  DV( height of viremia) : platelet direct activation and removal:
further activated by agonists like : ADP , ristocetin .
 Preexisting dengue ab augment the binding V-P
 Platelet destruction: Activation of complement at surface

16. Platelets have shown
• increased adhesiveness to dengue 2 virus infected human
endothelial cells :: activated phenotype :: destroyed

17. IMMUNE DESTRUCTION OF PLATELETS:

18. • Immune complex formation with DV Ag & their fixation
on platelet surface
• Presence of APA
• NS1 :: produce ab :: cross reacts with various integrin &
adhesion molecules

19. ACTIVATION OF COAGULATION
& CYTOKINE STORM

20. • DVI : activation of EC :: expression of tissue factor &
up-regulation of coagulant, anticoagulant , fibrinolytic
protein and their inhibitors

21. • Activated endothelial cells : platelet adhesion
• ultra HMW vWF : platelet aggregation

22. • Endothelial cell activation: increased synthesis of various
proteins => raise/increase pro inflammatory cytokines and
coagulant proteins

24. • Excessive activation of endothelial cells => classical DIC
with D Dimer positivity

25. LIVER
• Liver involvement in DV Infection:: reduced FVIII, XI
=> prolonged aPTT
• CYTOKINE STORM: monocytes, T lymphocytes , liver
cells & endothelial cells: aggravation of Coagulation
system

26. CYTOKINE STORM IN DENGUE VIRUS
INFECTION

27. • Pro inflammatory cytokines => rise and falls => different
stages of DF.
• IFN γ , TNF α, IL2, IL4, IL6, IL8, IL10 ,IL1b
• IL8 : capillary leak => DSS

28. • Higher cytokine storm during 2ο infection
=> higher load of viral infection in monocyte and
macrophages
=> due to antibody dependant enhancement

31. CONCLUSION
• DV related coagulation is multifactorial
1. DIRECT EFFECT OF VIRUS :
2. INDIRECT EFFECT ON COAGULATION:

32. DIRECT EFFECT OF VIRUS AS :
1. Virulence of virus : DEN 2 :: most hemorrhagic
2. Platelet Activation & removal
3. Endothelial cell activation removing activated platelets
4. Direct infection (megakaryocytic precursors) => apoptosis =>
reduced production of platelets
5. Liver infection => reducing synthesis of coagulation protein

33. INDIRECT EFFECT ON COAGULATION:
1. ADE of infection
2. Thrombocytopenia :: Immune complex and complement
activation
3. Liver injury : T lymphocyte
4. Cytokine storm :: liver , monocytes, T cells , EC
5. DIC