Mechanism of

Thrombocytopenia and
Coagulopathy in Dengue
Infection
Rahajuningsih Dharma
Departmen of Clinical Pathology
Faculty of Medicin University of Indonesia

Dengue hemorrhagic fever

2009
2005

1968
First case
DHF reported
in Surabaya

Total cases in
Indonesia
95.270 or 53%
of all cases in
South East Asia.
1298 fatal (CFR=
1.36%)

The total cases in

Indonesia 121. 423
with 1384 fatal
(CFR =0.98%)

WHO criteria 1997

Fever (2-7 days)

Bleeding (positive
tourniquet test )

Thrombocytopenia
(<100 000/uL)
Plasma leakage: (Ht
20%)

Bleeding manifestations
Subcutaneous
hemorrhages

Petechiae
Echymoses

Mucosal
bleeding
Gum
bleeding

GI tr. bleeding

Positive
tourniquet
test

Causes of bleeding
Thrombocytopenia
Platelet dysfunction
Coagulopathy

Vasculopathy

Mechanism of Thrombocytopenia
Consumption

Destruction

Aggregati
on

Direct
effect

DIC

Immunemediated

Production

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

In vitro study

Platelets interact
with DV- infected
endothelial cells

Platelets
Aggregation

Platelets
lysis

Funahara et al. South East Asian J Trop Med Pub Health 1987

Immune-mediated platelet destruction

Immune
complex

Complement activation
Membrane attack
complex lysis

Cross
reaction

Anti NS1 cross react

with GP IIbIIIa

Mechanism of Platelets dysfunction

Immune complex containing DV
activate

platelets

PF4 and thromboglobulin release

Platelets Exhaustion
platelets

dysfunction

Mechanism of coagulopathy

Acute DIC

Increased
Fibrinolysis

DIC

Definition

Laboratory
evidence

Systemic
thrombohemorrhagic
disorders associated with
well-defined clinical
situations
Coagulation and fibrinolytic
activation
Inhibitor consumption
Evidence of end-organ
damage

Bick RL. Disorders of thrombosis and hemostasis 2002

Clinical conditions associated with DIC

Obstetric
complications
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

Underlying condition

cytokines
TF mediated
Activation of
coagulation

Depression of
Inhibitory systems

PAI-1 mediated
inhibition of
fibrinolysis

Inadequate
Fibrin removal

Fibrin formation

Fibrin deposition

Organ failure
Levi 1999

Dengue Virus and cytokine

Endothelium loss its

nonthrombogenic

Expressing TF, vWF and PAI-1

Activate coag. platelet

Inhibit fibrinolytic

Intravascular thrombosis

consumption

bleeding

Mairuhu AT et al Lancet Infect Dis 2003; 3: 33-41

Laboratory findings in Acute DIC

Thrombocytopenia
Fragmented red cell +

PT >>
APTT >>
Fibrinogen
FDP D dimer
Funahara et al 1980

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 <5
compensated DIC
Repeat testing 1- 2
days

SSC ISTH 2001

Mechanism of Fibrinolysis
Fibrin bound plasminogen

Free plasminogen

PAI

Plasminogen activator
Fibrin bound plasmin

Antiplasmin

Free plasmin

PAP
complex

Fibrin

Fibrin / fibrinogen
degradation product

Fibrinogen
, F V, F VIII

Increased fibrinolysis
Fibrinogen
FDP

Antiplasmin

Plasmin-antiplasmin
complex

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 cross reactive antibody
Halstead S, Lancet 2007;370:1644-52

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

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 58
84).
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

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

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 and
13% in DF group
Sensitivity 90% and specificity 67% in
predicting severe DHF
Setrkraising et al Asian Biomedicine 2007; 1: 53-7

Summary
Thrombocytopenia:
Production
Destruction (complement dependent, cross
reactivity)
Consumption

Coagulopathy :
DIC
Fibrinolysis

Thank you