Sepsis

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.
 Causation in Sepsis
Initiators Predisposing
Microorganism Subclinical Promoters
Toxin
Enabling

1. Inflamatory respons 2. Activation of coagulation

3. Excessive inflammatory Mediators 4. Excessive coagulation activity

Dehydration

Shock MOD DIC

MOF

Death MOD=multiple organ dysfunction

MOF=multiple organ failure
 Causation in Sepsis
Initiators Predisposing
Mikroorganism Subclinical Promoters
Toksin
Enabling
1. Inflamatory respons
Precipitating Progressor
2. Coagulation activating
Clinical entity
3. Excessive Inflammatory Mediators
4. Excessive coagulation activity Dehydration

DIC or Shock or both Reinforcing Aggravators

Clinical worsening
MOD/MOF MOD=multiple organ dysfunction
MOF=multiple organ failure

Death
 Inflammatory Mediators
Bcell → IL-1β, IL-6, TNFα
Monocyte/macrophage → IL-1α, IL-6, TNFα
TNFα → 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 cells
IL-6 → multilineage proliferation, acute phase
protein by hepatocytes, osteoclast

LAF=leukocyte activating factor

Systemic Inflammatory Response
TNFα ↑ Syndrome :
IL-1 ↑  inhibit growth factor Hypotension
IL-6 ↑  multilineage growth factor
MOD
PMN→Elastase (TAF)→TF-III ↑
KKP systemKal-C1-Inh ↑C1-Inh
DIC
↓→ procoagulant activity ↑ and ARDS
plasminogen activator ↑ MOF
Complement → ↓
SIRS:
• Unconsidered causes
 Systemic Inflammatory Response Syndrome
• Considering causes by Microorganism
 Septic Inflammatory Response Syndrome
 Principle management

Stage Treatment
Inflamatory response by microorganism Antimicrobial
Excessive Mediators of inflamation Corticosteroid
Complement deficient 5S
Coagulation activation Anticoagulant
AT-III or PC
Excessive coagulation activity 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
 The coagulation pathway
Intrinsic pathway Extrinsic pathway
XII XIIa
TF
XI XIa
VIIa VII
PL
PS IXa Ca2+
IX
Legend
PC aPC VIIIa
TM Ca2+ Xa Coagulation
PL mechanisms
Xa X
Endogenous
Va TFPI
anticoagulant
PL ATIII
Ca2+ Inhibition
IIa by heparins
II
TF: tissue factor
PL: phospholipid Inhibition by
TFPI: tissue factor pathway inhibitor Fibrinogen Fibrin Vitamin K
PS: protein S antagonists
PC: protein C
1. Rosenberg RD, Aird WC. N Engl J Med. 1999;340:1555–1564
PCa: activated protein C 2. Hirsh J, et al. Chest. 1995;108(suppl):258–275S
TM: thrombomodulin
Clot 3. Samama CM et al. Thromb Haemost. July 2001. ISTH Abstract OC2343
4. Hirsh J, Fuster V. Circulation. 1994;89:1469–1480
ATIII: antithrombin III 5. Hirsh J, Fuster V. Circulation. 1994;89:1449–1468
 New agents acting on coagulation, the
search for selectivity
Coagulation pathway Late approaches in research

TF/VIIa  Tissue Factor Pathway Inhibitors

Initiation
TFPI, NAPc2
Thrombin X IX
 Factor IXa Inhibitors
generation IXa inhibitors, IXa antibody
IXa VIIIa • Protein C Activators
APC, thrombomodulin
• Factor Xa Inhibitors
Xa Va
AT-III, Pentasaccharide, direct Xa inhibitors
II

 Thrombin Inhibitors
Thrombin
IIa Hirudin, bivalirudin, argatroban,
activity
melagatran
TFPI = Tissue Factor Pathway Inhibitors
NAPc2 = Nematode Anticoagulant Protein C2
APC = Activated Protein C 1. Weitz J, Hirsh J. Chest. 2001;119:95–107S
AT III = Antithrombin III
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