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Mechanism ofThrombocytopenia and
Coagulopathy in Dengue
Infection
Rahajuningsih DharmaDepartmen of Clinical Pathology
Faculty of Medicin University of Indonesia
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Dengue hemorrhagic fever
1968
First caseDHF reported
in Surabaya
2005
Total cases inIndonesia95.270 or 53%of all cases inSouth East Asia.
1298 fatal (CFR=
1.36%)
2009The total cases inIndonesia 121. 423with 1384 fatal(CFR =0.98%)
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WHO criteria 1997
Fever (2-7 days)
Bleeding (positivetourniquet test )
Thrombocytopenia(
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Bleeding manifestations
Subcutaneous
hemorrhages
Petechiae
Echymoses
Mucosalbleeding
Gumbleeding
GI tr. bleeding
Positivetourniquettest
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Causes of bleeding
Thrombocytopenia
Platelet dysfunction
Coagulopathy
Vasculopathy
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Mechanism of Thrombocytopenia
Consumption
Aggregation
DIC
Destruction
Directeffect
Immune-mediated
Production
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Decreased production
Megakaryocyte
Precursor of erythrocyte
and myeloid
Direct effect of DV infection
on hematopoietic progenitor
Na Nakorn et al. Bulletin WHO 1966;25: 54-5
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Platelets interactwith DV- infectedendothelial cells
PlateletsAggregation
Plateletslysis
In vitro study
Funahara et al. South East Asian J Trop Med Pub Health 1987
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Immune-mediated platelet destruction
Complement activation
Membrane attack
complex lysis
Immune
complex
Anti NS1 cross reactwith GP IIbIIIa
Crossreaction
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Mechanism of Platelets dysfunction
Platelets Exhaustion
platelets dysfunction
PF4 and thromboglobulin release
Immune complex containing DV
activate platelets
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DIC
Systemicthrombohemorrhagicdisorders associated withwell-defined clinicalsituations
Definition
Coagulation and fibrinolyticactivation
Inhibitor consumption
Evidence of end-organdamage
Laboratoryevidence
Bick RL. Disorders of thrombosis and hemostasis 2002
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Clinical conditions associated with DIC
Obstetriccomplications
Intravascular
hemolysis
Sepsis:
Gram negative
Gram positive
Viremia HIV
Hepatitis
Dengue virus infection
Burns
Crush injuries
Trauma
Acute liver disease Obstructive jaundice
Acute hepatic failure
Prosthetic devices
Vascular disorders
Malignancy
Leukemia
Bick RL 2002
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Underlying condition
cytokines
TF mediated
Activation of
coagulation
Depression of
Inhibitory systems
PAI-1 mediated
inhibition of
fibrinolysis
Fibrin formationInadequate
Fibrin removal
Fibrin deposition
Organ failure Levi 1999
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Laboratory findings in Acute DIC
Thrombocytopenia
Fragmented red cell +
PT >> APTT >>
Fibrinogen
FDP D dimer
Funahara et al 1980
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Scoring system for diagnosis DIC
Platelet count ( x 103/uL):
< 100 = 0
50 100 = 1 < 50 = 2
Prolonged PT
< 3 seconds = 0
3 6 seconds = 1
> 6 seconds = 2
D dimer
No increase = 0
Moderate increase = 2
Strong increase= 3
Fibrinogen level
> 100 mg/dL = 0
< 100 mg/dL = 1
Total score 5
Overt DIC
Repeat testing
daily
Total score
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Mechanism of Fibrinolysis
Free plasminogenFibrin bound plasminogen
Fibrin bound plasmin
Free plasmin
Plasminogen activator
Fibrin
PAI
Antiplasmin
Fibrinogen, F V, F VIII
Fibrin / fibrinogendegradation product
PAP
complex
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Increased fibrinolysis
Fibrinogen FDP
Antiplasmin
Plasmin-antiplasmincomplex
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Coagulopathy
Underlying mechanism still remain unclear
Severe bleeding happens only rarely in children and
thrombotic complication are not seen
APTT >>, fibrinogen and thrombocytopenia
Evidence of classic DIC is not convincing
Fibrinolytic activity due to:
direct interaction between DV and plasminogen Plasminogen crossreactive antibody
Halstead S, Lancet 2007;370:1644-52
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Coagulation abnormalities in DHF: Serial
investigations in 167 Vietnamese Children with
DSS
DV directly activate fibrinolysis
Minor prolongation of PT and APTT
Fibrinogen
Protein C, Protein S and AT
Tissue Factor, Thrombomodulin , PAI -1
Wills BA, et al Clin. Infect Dis 2002;35:277-85
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Comparison of clinical features and
hematologic abnormalities between DF and
DHF among children in the Philippines
Thrombocytopenia was more prominent in
DHF group than DF group (113
58 vs 5884).
Low Fibrinogen levels in DHF group indicated
increased fibrinolysis
Summary : combination of thrombocytopenia
and increased fibrinolysis , not classic DIC
Carlos et al Am.J. Trp. Med. Hyg. 2005;73:435-40
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Fibrin formation and lysis studies in
dengue virus infection
Thrombin time >> (transient acquired
dysfibrinogenemia)
Fibrinogen level was normal (2.5 3.2 g/L)
FDP
Clot images obtained by scanning electron
microscopy showed fibrin network had some
degree of degradation Conclusion: hyperfibrinolysis could modify
fibrinogen molecule
Marchi et al Blood Coagul Fibrinolysis 2009; 20:575-82
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D-dimer as an indicator of dengue severity
D-dimer was determined using whole blood
and rapid semiquantitative (Simplired)
D-dimer was found in 87% in DHF group and13% in DF group
Sensitivity 90% and specificity 67% in
predicting severe DHF
Setrkraising et al Asian Biomedicine 2007; 1: 53-7
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Summary
Thrombocytopenia:
Production
Destruction (complement dependent, cross
reactivity)
Consumption
Coagulopathy :
DIC
Fibrinolysis
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hank you