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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
Fibrinolysis/Inhibitors
Coagulation Proteins
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
Fibrinolysis/Inhibitors
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
Fibrin Clot+ Platelet Plug
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
AnticoagulantInhibition
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
IntrinsicPathway(aPTT)
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
AnticoagulantInhibition
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
AnticoagulantInhibition
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
AnticoagulantInhibition
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
AnticoagulantInhibition
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
AnticoagulantInhibition
FactorXa
or
FactorII
Factor IIa(Thrombi
n)
AnticoagulantInhibition
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
AnticoagulantInhibition
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
Fibrinolysis/Inhibitors
Coagulation Proteins
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
IntrinsicPathway(aPTT)
Fibrinolysis
VIIIUre-
KinaseT-PA
Plas-minogen
Plasmin
CommonPathway
II Va
V
IIa
XIIIXIIIa
FibrinPolymer
Fibrin Clot+ Platelet Plug
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