Shufrie Effendy

SepsisSepsis

Shufrie Effendy

Division of Hematology-Medical Oncology,

Department of Internal Medicine, Faculty of Medicine University of Indonesia,

Dr. Cipto Mangunkusumo National Center Hospital /

Dharmais National Cancer Center Hospital,

Jakarta.

MicroorganismToxin

Predisposing

Enabling

Subclinical

MOD

Causation in SepsisCausation in Sepsis

Promoters

Death

Initiators

DIC

1. Inflamatory respons

3. Excessive inflammatory Mediators

MOD=multiple organ dysfunctionMOF=multiple organ failure

Dehydration

2. Activation of coagulation

4. Excessive coagulation activity

Shock

MOF

MikroorganismToksin

Predisposing

Enabling

Precipitating

Subclinical

Clinical entity

Reinforcing

Clinical worseningMOD/MOF

Causation in SepsisCausation in Sepsis

Progressor

Aggravators

Promoters

Death

Initiators

DIC or Shock or both

1. Inflamatory respons2. Coagulation activating

3. Excessive Inflammatory Mediators4. Excessive coagulation activity

MOD=multiple organ dysfunctionMOF=multiple organ failure

Dehydration

Inflammatory MediatorsInflammatory Mediators

Bcell → IL-1β, IL-6, TNFα Monocyte/macrophage → IL-1α, IL-6, TNFαTNFα → CD33+CD34- (Monocyte/macrophage, NK cells,

B/T Lymphocytes) → IL-1(LAF), IL-6, TNFα≠ CD33+CD34+

IL-1α → Fever, acute phase reactants,→ chemotaxis PMN,→ proliferation of Lymphocyte, Fibroblast,

Endothelial cellsIL-6 → multilineage proliferation, acute phase

protein by hepatocytes, osteoclast

LAF=leukocyte activating factor

Systemic Inflammatory ResponseSystemic Inflammatory Response

Syndrome :HypotensionMODDICARDSMOF

TNFα ↑IL-1 ↑ inhibit growth factorIL-6 ↑ multilineage growth factorPMN→Elastase (TAF)→TF-III ↑

KKP systemKal-C1-Inh ↑C1-Inh ↓→ procoagulant activity ↑ and plasminogen activator ↑Complement → ↓

SIRS:• Unconsidered causes

Systemic Inflammatory Response Syndrome• Considering causes by Microorganism

Septic Inflammatory Response Syndrome

Principle managementPrinciple management

StageStage TreatmentTreatment

Inflamatory response by microorganism Antimicrobial

Excessive Mediators of inflamation Corticosteroid

Complement deficient 5S

Coagulation activation Anticoagulant

Excessive coagulation activityAT-III or PC concentrate or rH-Thrombomodulin

DIC DIC protocol

Systemic circulation failure Shock protocol

Anti inflammatory response of Natural anticoagulant (AT-III & activated Protein C) by Limits the rolling of neutrophils and monocyte inhibit cytokine production

VIIIaCa2+

PL

IXa

The coagulation pathwayThe coagulation pathway

Clot

Intrinsic pathway Extrinsic pathway

TM

TF

Ca2+

Xa

TFPI

aPCPC

PS

X

II

IX

XI

XII XIIa

FibrinFibrinogen

VaPL

Ca2+

IIa

VII

Inhibition by heparins

Inhibition by Vitamin Kantagonists

Coagulation mechanisms

Xa

Endogenous anticoagulant

ATIII

XIaVIIa

1. Rosenberg RD, Aird WC. N Engl J Med. 1999;340:1555–15642. Hirsh J, et al. Chest. 1995;108(suppl):258–275S

3. Samama CM et al. Thromb Haemost. July 2001. ISTH Abstract OC23434. Hirsh J, Fuster V. Circulation. 1994;89:1469–1480 5. Hirsh J, Fuster V. Circulation. 1994;89:1449–1468

TF: tissue factor

PL: phospholipid

TFPI: tissue factor pathway inhibitor

PS: protein S

PC: protein C

PCa: activated protein C

TM: thrombomodulin

ATIII: antithrombin III

Legend

PL

Thrombin Inhibitors Hirudin, bivalirudin, argatroban,

melagatran

Factor IXa InhibitorsIXa inhibitors, IXa antibody

• Protein C Activators APC, thrombomodulin• Factor Xa Inhibitors AT-III, Pentasaccharide, direct Xa inhibitors

Coagulation pathway Late approaches in research

Tissue Factor Pathway Inhibitors TFPI, NAPc2

Initiation

Thrombingeneration

Thrombinactivity

TF/VIIa

IIa

II

Xa

IXa

IXX

VIIIa

Va

New agents acting on coagulation, the New agents acting on coagulation, the search for selectivitysearch for selectivity

1. Weitz J, Hirsh J. Chest. 2001;119:95–107S

TFPI = Tissue Factor Pathway InhibitorsNAPc2 = Nematode Anticoagulant Protein C2APC = Activated Protein CAT III = Antithrombin III

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