Transcript Document 7651158

Friction force
vWF
platelet
Coagulation
Factor
platelet
platelet
fibrin
platelet
Antithrombotic
pathway
platelet
Fibrinolytic
pathway
platelet
contact
Pathway
Tissue f.
Pathway
TFPI
X
AT III
pathway
Protein C
pathway
V
Thrombin
Fibrinogen
FDP
D-dimer
Fibrinolytic Pathway
plasminogen
Hemarthrosis
Hemophilia
혈우병
Pathologic bruising
in von Willebrand’s disease
platelet (혈소판)
vessel (혈관)
Intrinsic
pathway
Tissue
Factor
HMKN
PK
Activator
Kaolin
Silica
12
7
Extrinsic
pathway
Tissue Factor
thromboplastin
11
9
8
Platelet
phospholipid
10
Common
pathway
5
2
thrombin
1
fibrinogen
Fibrin
clot
Intrinsic
Pathway
Extrinsic
Pathway
12
11
9
8
X
ATIII
V
Thrombin
Fibrinogen
Fibrin
Protein C
Protein S
Antithrombin III pathway
7
12
Heparin
+
ATIII
11
9
8
+
Heparin like Substance
10
+
5
HCII
2
+
Dermatan Sulfate
Protein C pathway
7
12
11
9
aVIII
8
10
5
2
aV
PC + Thrombomodulin
+
APC resistence
Factor V Leiden:
Arg506Gln
Thrombin
Activated PC
+
PS free
PS free -- PS + C4b-BP
* Thrombomodulin:
thrombin receptor
on endothelial cell
* Cleavage site of Factor V
306,506,679
Damaged endothelial cell
Tissue
factor
VWf
7
12
PF4
11
9
activated
PLT
8
Tissue Factor
Pathway Inhibitor
10
5
2
Beta-TG
Antithrombin
Tissue
Factor
Pathway
Inhibitor
4
major
antithrombotic
pathways
Fibrinolytic System
Protein C
Protein S
Thrombi (혈전)
Thromboemboli
Hypercoagulable state
Protein C
Protein S
Antithrombin III
Plasminogen
Factor V Leiden
Collagen
fibronectin
VWf
GpIb
VWf
fibrinogen
receptor
PLT
GpIIb/IIIa
Factor VIII
Factor VIII and VWF terminology
Old term
Factor VIII
Protein
Antigen
Function
vWF
Protein
Antigen
Function
VIII:C
VIIIC:Ag
VIIIR:Ag
VIIIR:Ag
VIIIR:RCo
New term
VIII
VIII:Ag
VIII:C
VWF
VWF:Ag
VWF Activity
Damaged endothelial cell
VWf
PF4
bacterial glycopeptide
ristocetin
viper venome protein
activated
PLT
Beta-TG
Gp IIb/IIIa receptor
IIb
IIIa
Heterodimer
Transmembrane domain
Intracytoplasmic tail domain
Intracellular actin cytoskeleton organization
fluxes in intracellular Ca
pH
focal adhesion kinase
세포의 기능
motility
growth
분화
Gp IIb /IIIa
Decrease amount of Gp IIb/IIIa
Genetic defect of Gp IIb/IIIa
Platelet aggregation test
absence of response to ADP, collagen, epinephrine
impaired response to ristocetin
Collagen
fibronectin
VWf
GpIb
VWf
fibrinogen
receptor
PLT
GpIIb/IIIa
Factor VIII
Gp Ib
Platelet adhesion to damaged vessel
subendothelial matrix - vWF - GpIb
sheet formation
Genetic defect of Gp Ib gene:
Bernard Soulier syndrome
Platelet aggregation test
impaired response to ristocetin
normal response to ADP, collagen, epinephrine
Fibrinogen
FpA
X
Y+D
D E
Fibrin monomer
D
D
E
Fibrin polymer
F.XIII
Fibrin clot
Plasminogen system
YY/DYD
YD/DY
DD/E
D-dimer
Plasminogen activator Plasminogen
Plasmin
Fibrin
Fibrin
A1-antiplasmin + plasmin
A1-antiplasm
Plasminogen System
fibrinolytic system
•• Vascular
biology
Matrix remodelling
•• Tumor
growth
Dissemination of tumor
• Wound healing
Single Cell Vital Organ
Friction force
Inflammatory cytokine
Growth factor
Circulating hormons
Bacterial product
Shear stress
Hydrostatic pressure
Cyclic strain
Endothelial cell
Gross modification of cell shape
Reorganization of cytoskeletal elements
SSRE expression
Differential display of mRNA transcript
vasoprotective
anti-atherogenic
Anti-thromboptic
anti-adhesive
anti-proliferative
anti-oxidant
eNOS (endothelial isoform of nitric oxide synthetase)
COX-2 (inducible isoform of cyclo-oxygenase)
MnSOD (manganase-dependent superoxide dismutase)
Platelet test
• Bleeding time
• Platelet count
• Platelet adhesion test
• Platelet aggregation test
•
ADP, epinephrine, collagen, ristocetin
Gp IIb/IIIa receptor measurement
Screening test for coagualtion pathway
• Platelet count
• Bleeding Time
• PT, aPTT, fibrinogen
• Thrombin time
Diagnostic tests: Coagulation assay
• factor I, II, V, VII, VIII, IX, X, XII
• prekallikrein
• HMWK
• factor XIII
Fibrinolytic system test
• Fibrinogen, FDP, D-dimer
• Plasminogen, Plasminogen activator
• Plasminogen activator inhibitor
• a2-antiplasmin
Antithrombotic pathway
• Antithrombin III
• Protein C, Protein S
• Factor V Leiden
• Plasminogen
HMKN
PK
Tissue Factor
12
7
11
9
8
10
5
Heparin
+
ATIII
2
thrombin
1
fibrinogen
Fibrin
clot
PT
APTT
Tissue
Factor
HMKN
PK
12
Activator
Kaolin
Silica
7
11
9
8
Platelet
phospholipid
10
5
CaCl2
CaCl2
2
1
Fibrin
clot
Tissue Factor
thromboplastin
왜 aPTT만을 기준으로 할 수 없는지?
aPTT의 증가 : 효과적으로 anticoagulation
되었다고 판단할 수 없다.
aPTT 검사 방법, 시약 종류, 검사 기기에 따른 차이 :
standardized method 라는 것이 없다는 문제점
Heparin 종류에 따른 차이:
종류가 다른 약을 사용할 경우 같은
aPTT 수치를 보여도 antithrombotic effect는 현저히 다르다.
Surrogate assay for heparin concentration
History of Heparin Monitoring
1967 JAMA : Replacement of WBCT by aPTT
1972 NEJM : Historical TR of ratio of 1.5 - 2.5
1st prospective clinical study
1977 Blood : TR 0.2 - 0.4 U/ml by protamine titration
1986 NEJM : TR 0.3 - 0.7 U/ml by anti-Xa activity
‘ Gold Standard’
Reports on the problems in using Fixed Ratio
d/t different responsiveness of different reagents
1980, 1985, 1988, 1990 AM J Clin Pathol
1990 Thromb Haemost
Anti-Xa Heparin Assay
Free AT + Heparin -> AT-Heparin
AT-Heparin + Fxa (in excess) ->
AT-Heparin-Fxa + Fxa (residual)
Fxa (residual) + Substrate -> Signal
Heparin 투여 환자에서 사용전 점검할 항목
Platelet Count
Heparin antibody screening
AT III level
Consensus Recommendations : HIT
Heparin 투여환자의 혈소판수 검사
- Naïve paient
투여전 & 투여 4일후부터 격일로 14일간 혈소판수 검사
- prior heparin exposure
투여전 & 투여 1일째부터 격일로 14일간 혈소판수 검사
Confirm by assay for heparin mediated antibody if
- 혈소판수치가 heparin 투여전의 50% 이하로 감소
혈소판 수<100,000/ul
- 혈소판 수치가 감소하지 않더라도 arterial or venous thrombosis가
진행될 경우
Q & A about LMWH
LMWH은 UH와 무엇이 다른가?
US: mixture of polysacchride chains(3,000-30,000)
LMWH: UH의 분획, potent anti-Xa activity
LMWH의 장점은?
Decreased binding to nonanticoagulant-related plasma protein
Greater bioavailability
longer half life
lower incidence of HIT
Predictable anticoagulant activity: No monotoring
LMWH injection route
Subcutaneous injection (self)
PT
APTT
Tissue
Factor
HMKN
PK
12
Activator
Kaolin
Silica
7
11
9
8
Platelet
phospholipid
10
5
CaCl2
CaCl2
2
1
Fibrin
clot
Tissue Factor
thromboplastin
Prothrombin Time (PT)
• sec
•%
• International Normalized Ratio
정상 0.8 - 1.2
Therapeutic Range 2.0 - 3.0
Anticoagulant
Warfarin
복용환자의 뇌출혈
Therapeutic Range
monitor
by PT