hemostaz yard. doç. dr. murat Örmen. vessels platelets fibrinolysis/inhibitors coagulation...

HEMOSTAZHEMOSTAZ

Yard. Doç. Dr. Murat ÖRMENYard. Doç. Dr. Murat ÖRMEN

Vessels

Platelets

Fibrinolysis/Inhibitors

Coagulation Proteins

Bleeding Clotting

Hemostaz

Endothelial Cells Basement Membrane

Red Blood Cells Platelets White Cells

Vascular SystemVascular System

Platelets



Vessels

PRİMER HEMOSTAZ

Platelet Rich Plasma (PRP)

Aggregating Reagent

AggregateClumping

Baseline Light Transmission

Increased LightTransmission

+

Platelet AggregationPlatelet Aggregation

Function HEMOSTASİS Function HEMOSTASİS BLEEDİNG AGREGOMETRİ BLEEDİNG AGREGOMETRİ

ANİMASYONANİMASYON

PlateletsCoagulation Proteins


Vessels

Fibrinogen

VIIExtrinsicPathway

(PT)

TissueFactor

Kinins

XX

IX

XI

XII

HMWK Prekalli-krein

Kalli-krein

XIIa

XIa

IXa

VIIIaXa

VIIa

Pro-Urokinase

IntrinsicPathway(aPTT)

Fibrinolysis

VIIIUre-

KinaseT-PA

Plas-minogen

Plasmin

CommonPathway

II Va

V

IIa

XIIIXIIIa

FibrinPolymer

Fibrin Clot+ Platelet Plug

ExtrinsicPathway

(PT)

CommonPathway

Fibrinigen

VII

XXa

VIIa

II Va

V

IIa

XIIIXIIIa

FibrinPolymer

TissueFactor


Ca++

Ca++

Phospholipid(Platelet Factor 3)

HighMolecular

WeightKininogen

Factor VIIa

Factor VIIa

TissueFactor

FactorXa

TFPI*TFPI*

FactorXa

FactorXIIa

FactorIXa

or or

ProcoagulantActivation

Procoagulant

AnticoagulantInhibition

FactorVII

*Tissue Factor Pathway Inhibitor

Factor VIIProconvertin,Stable Factor

Biosynthesis: Liver, Vitamin K dependentMW: 55,000 daltonsPlasma Concentration: 1 mg/LIn Vivo Half-Life: 5 hoursPathology: Hypoproconvertinemia, autosomal recessive

FactorVIIIa

TissueFactor

Phospholipid (PlateletFactor 3)

FactorIXa

FactorVIIa

Factor X Factor Xa

Factor Xa

Anti-

thrombin

IIIHeparin

Anti-thrombin

III

Ca++

Ca++

Heparin

Activation

Procoagulant


or

ExtrinsicX-aseComplex

IntrinsicX-ase

Complex

Tissue FactorFactor III,

Thromboplastin

Biosynthesis: Brain, lung,

subendotheliumMW: 45,000 daltons

Factor XStuart-Prower Factor

Biosynthesis: Liver, Vitamin K dependentMW: 55,000 daltonsPlasma Concentration: 5 mg/LIn Vivo Half-Life: 65 hours Pathology: Stuart disease, autosomal recessive

Fibrinogen

Kinins

X

IX

XI

XII

HMWKPrekalli-

kreinKalli-krein

XIIa

XIa

IXa

VIIIaXa


VIII

CommonPathway

II Va

V

IIa

XIIIXIIIa

FibrinPolymer Fibrin Clot

+ Platelet Plug

HighMolecular

WeightKininogen

NegativelyCharged

Activating Surface

(e.g., kaolin,ellagic acid

silica)Kalli-krein

FactorXII

Kinins

High Blood Pressure

and Inflammation

FactorXIIa

HMWK

C1 EsteraseInhibitor

C1

Esterase

Inhibitor

FactorXIIa

* FXIIf alter vascular permeability

Factor XIIFragments*

Activation

Procoagulant


High Molecular WeightKininogen (HMWK)Fitzgerald Factor

MW: 120,000 daltonsPlasma Concentration: 70 mg/LPathology: Fitzgerald trait,autosomal recessive

Factor XIIHageman Factor

Biosynthesis: LiverMW: 80,000 daltonsPlasma Concentration: 29 mg/LIn Vivo Half-Life: 60 hoursPathology: Hageman trait, autosomal recessive

Ca++

HighMolecular

WeightKininogen

FactorXIIa

Kallikrein

Prekalli-krein

Kalli-krein

Activation

Procoagulant


C1

Esterase

Inhibitor

C1 EsteraseInhibitor

PrekallikreinFletcher Factor

Biosynthesis: Probably LiverMW: 107,000 daltonsPlasma Concentration: 50 mg/LPathology: Fletcher trait, autosomal recessive

Ca++

HighMolecular

WeightKininogen

FactorXIIa

FactorXIa

Factor XI

FactorXIa

Activation

Procoagulant


1-

Anti-

trypsin

1- Anti-

trypsin

Factor XIPlasma ThromboplastinAntecedent

Biosynthesis: LiverMW: 158,000 daltonsPlasma Concentration: 4 mg/LIn Vivo Half-Life: 65 hoursPathology: Hemophilia C, autosomal recessive

Ca++

Ca++TissueFactor Factor

VIIa

FactorIXa

Factor IX

FactorIXa

Activation

Procoagulant


FactorXIaor

Anti-

thrombin

IIIHeparin

Anti-thrombin

IIIHeparin

Factor IXChristmas Factor

Biosynthesis: Liver, Vitamin K dependentMW: 57,000 daltonsPlasma Concentration: 4 mg/LIn Vivo Half-Life: 20 hours Pathology: Hemophilia B, (Christmas disease) x-linked recessive

Factor VIIIAntihemophilic FactorvWFvon Willebrand Factor

Biosynthesis: Liver, endothelium; Factor VIII Related Antigen, megakaryocyteMW(FVIII + vWF): 1.2-2 million daltons (6-10 subunits – 200,000 daltons each)Plasma Concentration: 7 mg/L (vWF)In vivo Half-Life: 10 hours (Factor VIII)Pathology: Factor VIII-Hemophilia A, x-linked recessive. vWF-von Willebrand’s disease, autosomal dominant

FactorIIa

FactorVIII

ActivatedProtein C

ProteinSPhospholipi

d(Platelet Factor 3)

InactiveFragments

Ca++

FactorVIIIa

Protein CComplex

Activation

Procoagulant


FactorXa

or

FactorII

Factor IIa(Thrombi

n)


Phospholipid(PlateletFactor 3)

Activation

Procoagulant

Factor Va Factor

Xa

Ca++

*or Heparin Cofactor II

Prothrombinase Complex

FactorIIa

Anti-

thrombin

III

Heparin

Anti-thrombin

IIIHeparin*

Activation Fragments

Factor IIProthrombin

Biosynthesis: Liver, Vitamin K dependentMW: 70,000 daltonsPlasma Concentration: 100 mg/LIn Vivo Half-Life: 100 hoursPathology: Hypoprothrombinemia, autosomal recessive

FactorIIa

FactorV

ActivatedProtein

CProtein

SPhospholipid

(Platelet Factor 3)

InactiveFragments

Ca++

Factor

Va

Protein CComplex

Activation

Procoagula nt


Factor VProaccelerin, Labile Factor

Biosynthesis: Liver, megakaryocytesMW: 330,000 daltonsPlasma Concentration: 5-12 mg/LIn Vivo Half-Life: 25 hoursPathology: Parahemophilia, autosomal recessive

Fibrinogen Factor I

Biosynthesis: LiverMW: 340,000 daltonsPlasma Concentration: 2500 mg/LIn Vivo Half-Life: 20 hoursPathology: Afibrinogenemia, autosomal recessive. Dysfibrinogenemia, autosomal dominant

FactorIIa Factor

IIa

Fibrinopeptide A

Fibrinopeptide B

FibrinogenFactor II

FibrinMonomerProcoagulant

ProcoagulantActivation

Activation

FactorIIa

Activation ActivationProcoagulant

FibrinPolymer

CA+

FactorXIII

FactorXIIIaSoluble

FibrinPolyme

r

Plasmin

Plasmin

Plasmin

Anticoagulant

Anticoagula

nt

Anticoagulant

Anticoag

ulant

Inhibition Inhi

bitio

n

Inhib

ition

Inhibition

Procoagulant

Activation

Fibrin(Factor

Ia)

Stable Thrombus

(Clot)

Activated

Platelets

FDPsFibrinogen

Degradation Products

FDPs & XDPs(Cross-linked DPs)

(e.g. D-dimers)

Factor XIIIFibrin Stabilizing Factor

(FSF)

Biosynthesis: Megakaryocytes, liver

MW: 320,000 daltonsPlasma Concentration: 10mg/L

In Vivo Half-Life: 12 daysPathology: FSF deficiency,

autosomal recessive

Thromboplastinand Calcium

Patient’s Plasma

Factors

IIIVVIIX

Prothrombin TimeProthrombin Time

Ca++

Patient’s Plasma

FactorsIIIV

VIIIIXXXIXII

Phospholipidand Activator

Activated PartialActivated PartialThromboplastin TimeThromboplastin Time

Quantitative FibrinogenQuantitative Fibrinogen

Highconcentrationof thrombin

1:10 dilutionpatient’splasma

Tim

e (

in s

e co

nd

s)

Fibrinogen in mg/dL

20 40 60 100 200 400 600

60

30

10

6

3

1:40 1:3

0 1:20

1:10

1:5

Heparin/AT-III ComplexHeparin/AT-III Complex

Minimum Plasma LevelsMinimum Plasma Levels

MinorMajor

Factor SpontaneousTrauma

Hemorrhageor Surgery

I Fibrinogen 50-100100 mg/dL

II 10-1520-40%

V 5-1525%

VII 5-1010-20%

VIII 5-1010-20%

Hemophilia A 15-2025%

von Willebrand 2525%

IX 10-1520-25%

X 5-1015-20%

XI 5-1515-25%

XII 1010%

XIII 15%

Williams, W. J., Hematology, 1972

Platelets



Vessels

FibrinolysisFibrinolysis

Activators: t-PA,u-PA, STK, XII, HMWK, PK

Plasminogen Plasmin

Fibrinogen Fibrin

Degradation Products

R.E.S.

PlasminogenBiosynthesis: LiverMW: 90,000 daltonsPlasma Concentration: 120 mg/LIn Vivo Half-Life: 48 hoursPathology: Plasminogen deficiency, autosomal dominant. Dysplasminogenemia, autosomal recessive

UrokinaseKallikrein

tPA(tissue

PlasminogenActivator)

Plasminogen

2 - Anti-

plasmin

2 - Anti-plasmin

Activation

Procoagulant

Anticoagulant

Inhibition

Plasmin

Plasmin

or or

Fibrinogen

VIIExtrinsicPathway

(PT)

TissueFactor

Kinins

XX

IX

XI

XII

HMWK Prekalli-krein

Kalli-krein

XIIa

XIa

IXa

VIIIaXa

VIIa

Pro-Urokinase


Fibrinolysis

VIIIUre-

KinaseT-PA

Plas-minogen

Plasmin

CommonPathway

II Va

V

IIa

XIIIXIIIa

FibrinPolymer


Antithrombin-III Inhibitionof Thrombin

Thrombin, Antithrombin-III and Heparin

HeparinLysine Site

Acidic Site

Arginine Site

Serine SiteThrombin(Active)

Antithrombin-III(Nonactivated)

Inactivation of Thrombin

Thrombin(Inhibited)

Heparin

Antithrombin-IIIHeparin Thrombin Complex

Antithrombin-III(Complexed)

Antithrombin-IIIDecreased Levels

1. Congenital

2. Acquired – decreased synthesis

3. Acquired – increased utilization

4. Drug-induced

Protein CProtein C

• Vitamin K-dependent plasma protein

• Inactivates Factors V and VIII

• Stimulates fibrinolysis

Protein CBiosynthesis: Liver, Vitamin K dependentMW: 56,000 daltonsPlasma Concentration: 3-5 mg/LIn Vivo Half-Life: 6-7 hours Pathology: Protein C deficiency, autosomal recessive (?)

* Requires Protein S for functional activity

Thrombo-modulin

FactorIIa

Protein C

ActivatedProtein C

Protein CInhibitor

Protein CInhibitor

ActivatedProtein

C*

Protein CActivation

Peptide

Activation

Procoagulant

Anticoagulant

Inhibition

Deficiencies of Protein CDeficiencies of Protein C

I. Congenital Hereditary autosomal dominantII. Acquired

A. DICB. Liver diseaseC. During post-operative periodD. Anticoagulant therapy

Clinical ManifestationsClinical Manifestations

• Superficial thrombophlebitis

• Venous thromboses in adolescents or young adults

• Arterial thromboses rarely observed

• Skin necrosis during onset of oral anticoagulant therapy

Protein SProtein S

• Cofactor for Protein C

• Vitamin K-dependent protein

• Enhances binding of Protein C to phospholipid surfaces

hemostaz yard. doç. dr. murat Örmen. vessels platelets fibrinolysis/inhibitors coagulation...

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