3.2. Mekanisme Trombositopenia Dan Kelainan Koagulasi Pada Infeksi Denguet

Mechanism of Thrombocytopenia hrombocytopenia and Coagu Coagulo lopa path thy y in Deng Dengue ue Infection Raha Rahaju juni ning ngsi sihh Dharm Dharma  a   Departmen of Clinical Pathology  Facul Fa culty ty of Medic Medicin in Univer Universi sity ty of Indonesi ndonesia  a 

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

Cross reaction

• Complement activation • Membrane attack

complex

lysis

• 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 • Systemic

Definition

thrombohemorrhagic disorders associated with well-defined clinical situations • Coagulation and fibrinolytic

Laboratory evidence

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

•

Burns

•

Crush injuries

•

Trauma

•

Acute liver disease

Sepsis:  –

Gram negative

 –

Gram positive

Viremia  –

 –

 –

HIV Hepatitis Dengue virus infection

 –

Obstructive jaundice

 –

Acute hepatic failure

•

Prosthetic devices

•

Vascular disorders

•

Malignancy

•

Leukemia

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

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  –

 –

 –

 –  –

•

 –

•

•

Repeat testing daily

Total score <5  –

 –  –

Overt DIC

 –

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 ↑ ↑