CoagulationFactor

Friction force

fibrinplatelet platelet platelet

platelet platelet

platelet

Antithrombotic pathway

Fibrinolytic pathway

vWF

contactPathway

Tissue f.Pathway

XV

Thrombin

Fibrinogen

FDP D-dimer

AT IIIpathway

Protein Cpathway

Fibrinolytic Pathwayplasminogen

TFPI

Hemarthrosis

Hemophilia혈우병

Pathologic bruisingin von Willebrand’s disease

platelet ( 혈소판 )vessel ( 혈관 )

12

11

9 8

10

5

2

1

7

Fibrinclot

TissueFactorHMKN

PKIntrinsicpathway

Extrinsicpathway

Commonpathway

thrombin

fibrinogen

ActivatorKaolinSilica

Plateletphospholipid

Tissue Factorthromboplastin

IntrinsicPathway

ExtrinsicPathway

XV

Thrombin

FibrinogenFibrin

1211

98

Protein CProtein SATIII

Antithrombin III pathway

Heparin+

ATIII+

Heparin like Substance+

HCII+

Dermatan Sulfate

12

119

8

10

7

52

PC + Thrombomodulin

* Thrombomodulin: thrombin receptor on endothelial cell

Thrombin+

PS free -- PS + C4b-BP

Activated PC+

PS free

aVIII

aV

APC resistenceFactor V Leiden:

Arg506Gln

* Cleavage site of Factor V 306,506,679

1211

98

10

7

52

Protein C pathway

activated

VWf

PLT

PF4

Beta-TG

1211

9

8

10

7

52

Tissuefactor

Damaged endothelial cell

Tissue FactorPathway Inhibitor

4major

antithromboticpathways

Antithrombin

Protein CProtein S

TissueFactorPathwayInhibitor

Fibrinolytic System

Hypercoagulable stateProtein CProtein S

Antithrombin IIIPlasminogen

Factor V Leiden

Thrombi ( 혈전 )Thromboemboli

GpIbreceptor

Collagen fibronectin

fibrinogen

GpIIb/IIIa

VWf VWf Factor VIII

PLT

Old term New term

Factor VIII Protein Antigen Function

vWF Protein Antigen Function

VIII:C VIIIC:Ag

VIIIVIII:AgVIII:C

VIIIR:AgVIIIR:Ag

VIIIR:RCo

VWF VWF:Ag

VWF Activity

Factor VIII and VWF terminology

activated

VWf

PLT

PF4

Beta-TG

Damaged endothelial cell

bacterial glycopeptideristocetin

viper venome protein

Gp IIb/IIIa receptor

IIb

Transmembrane domain

Intracytoplasmic tail domain

Heterodimer

Intracellular actin cytoskeleton organizationfluxes in intracellular Ca

pHfocal adhesion kinase

세포의 기능motilitygrowth분화

IIIa

Gp IIb /IIIa

Decrease amount of Gp IIb/IIIaGenetic defect of Gp IIb/IIIa

Platelet aggregation testabsence of response to ADP, collagen, epinephrineimpaired response to ristocetin

GpIbreceptor

Collagen fibronectin

fibrinogen

GpIIb/IIIa

VWf VWf Factor VIII

PLT

Gp Ib

Platelet adhesion to damaged vesselsubendothelial matrix - vWF - GpIbsheet formation

Genetic defect of Gp Ib gene:Bernard Soulier syndromePlatelet aggregation test impaired response to ristocetin normal response to ADP, collagen, epinephrine

Fibrinogen

Fibrin monomer

Fibrin polymer

Fibrin clot

X

Y+DD E

YY/DYDYD/DYDD/E

D-dimer

FpA

D DE

Plasminogen system

F.XIII

Plasminogen activator Plasminogen Plasmin A1-antiplasm

Fibrin Fibrin

A1-antiplasmin + plasmin

Plasminogen Systemfibrinolytic system

• Vascular biology• Matrix remodelling• Tumor growth• Dissemination of tumor• Wound healing

Inflammatory cytokineGrowth factorCirculating hormonsBacterial productShear stressHydrostatic pressureCyclic strain

Gross modification of cell shapeReorganization of cytoskeletal elementsSSRE expressionDifferential display of mRNA transcript

eNOS (endothelial isoform of nitric oxide synthetase)COX-2 (inducible isoform of cyclo-oxygenase)MnSOD (manganase-dependent superoxide dismutase)

vasoprotective anti-atherogenic

Anti-thrombopticanti-adhesiveanti-proliferativeanti-oxidant

Friction force

Single Cell Vital Organ

Endothelial cell

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

1211

9 8

10

5

2

1

7

Fibrinclot

Tissue FactorHMKNPK

thrombin

fibrinogenHeparin

+ATIII

1211

9 8

10

5

2

1

7

Fibrinclot

TissueFactorHMKN

PK

APTT

ActivatorKaolinSilica

Plateletphospholipid

CaCl2

Tissue Factorthromboplastin

CaCl2

PT

aPTT 의 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 effect 는 현저히 다르다 .

Surrogate assay for heparin concentration

왜 aPTT 만을 기준으로 할 수 없는지 ?

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 Ratiod/t different responsiveness of different reagents1980, 1985, 1988, 1990 AM J Clin Pathol1990 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

Platelet Count

Heparin antibody screening

AT III level

Heparin 투여 환자에서 사용전 점검할 항목

Heparin 투여환자의 혈소판수 검사

- Naïve paient 투여전 & 투여 4 일후부터 격일로 14 일간 혈소판수 검사

- prior heparin exposure 투여전 & 투여 1 일째부터 격일로 14 일간 혈소판수 검사

Consensus Recommendations : HIT

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 thrombosis 가 진행될 경우

LMWH 은 UH 와 무엇이 다른가 ?US: mixture of polysacchride chains(3,000-30,000)LMWH: UH 의 분획 , potent anti-Xa activity

Q & A about LMWH

LMWH 의 장점은 ?Decreased binding to nonanticoagulant-related plasma proteinGreater bioavailabilitylonger half lifelower incidence of HITPredictable anticoagulant activity: No monotoring

LMWH injection routeSubcutaneous injection (self)

1211

9 8

10

5

2

1

7

Fibrinclot

TissueFactorHMKN

PK

APTT

ActivatorKaolinSilica

Plateletphospholipid

CaCl2

Tissue Factorthromboplastin

CaCl2

PT

Prothrombin Time (PT)

• sec• %• International Normalized Ratio

정상 0.8 - 1.2 Therapeutic Range 2.0 - 3.0

AnticoagulantWarfarin

복용환자의 뇌출혈

Therapeutic Rangemonitorby PT