3.2. Mekanisme Trombositopenia Dan Kelainan Koagulasi Pada Infeksi Denguet

8/10/2019 3.2. Mekanisme Trombositopenia Dan Kelainan Koagulasi Pada Infeksi Denguet

1/26

Mechanism ofThrombocytopenia and

Coagulopathy in Dengue

Infection

Rahajuningsih DharmaDepartmen of Clinical Pathology

Faculty of Medicin University of Indonesia


2/26

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%)


3/26

WHO criteria 1997

Fever (2-7 days)

Bleeding (positivetourniquet test )

Thrombocytopenia(


4/26

Bleeding manifestations

Subcutaneous

hemorrhages

Petechiae

Echymoses

Mucosalbleeding

Gumbleeding

GI tr. bleeding

Positivetourniquettest


5/26

Causes of bleeding

Thrombocytopenia

Platelet dysfunction

Coagulopathy

Vasculopathy


6/26

Mechanism of Thrombocytopenia

Consumption

Aggregation

DIC

Destruction

Directeffect

Immune-mediated

Production


7/26

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


8/26

Platelets interactwith DV- infectedendothelial cells

PlateletsAggregation

Plateletslysis

In vitro study

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


9/26

Immune-mediated platelet destruction

Complement activation

Membrane attack

complex lysis

Immune

complex

Anti NS1 cross reactwith GP IIbIIIa

Crossreaction


10/26

Mechanism of Platelets dysfunction

Platelets Exhaustion

platelets dysfunction

PF4 and thromboglobulin release

Immune complex containing DV

activate platelets


11/26


12/26

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


13/26

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


14/26

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


15/26


16/26

Laboratory findings in Acute DIC

Thrombocytopenia

Fragmented red cell +

PT >> APTT >>

Fibrinogen

FDP D dimer

Funahara et al 1980


17/26

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


18/26

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


19/26

Increased fibrinolysis

Fibrinogen FDP

Antiplasmin

Plasmin-antiplasmincomplex


20/26

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


21/26

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


22/26

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


23/26

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


24/26

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


25/26

Summary

Thrombocytopenia:

Production

Destruction (complement dependent, cross

reactivity)

Consumption

Coagulopathy :

DIC

Fibrinolysis


26/26

hank you

3.2. Mekanisme Trombositopenia Dan Kelainan Koagulasi Pada Infeksi Denguet

Documents

Transcript of 3.2. Mekanisme Trombositopenia Dan Kelainan Koagulasi Pada Infeksi Denguet