Hemostaz - mustafaaltinisik.org.uk

HEMOSTAZ
Yard. Doç. Dr. Murat ÖRMEN
Hemostaz
Vessels
Bleeding
Clotting
Coagulation
Proteins
Platelets
Fibrinolysis/Inhibitors
Vascular System
Endothelial Cells
Red Blood Cells
Basement Membrane
Platelets
White Cells
Vessels
Coagulation
Proteins
Platelets
Fibrinolysis/Inhibitors
PRİMER HEMOSTAZ
Platelet Aggregation
Platelet
Rich
Plasma
(PRP)
+
Baseline Light
Transmission
Aggregatin
g Reagent
Aggregat
e
Clumping
Increased
Light
Transmission
Function HEMOSTASİS BLEEDİNG
AGREGOMETRİ ANİMASYON
Vessels
Coagulation
Proteins
Fibrinolysis/Inhibitors
Platelets
HMWK Prekalli-
VII
Extrinsic
Pathway
(PT)
Kallikrein
krein
Kinins
XII
XIIa
Tissue
Factor
XIa
Intrinsic
Pathway
(aPTT)
XI
VIIa
IXa
IX
X
II
Xa
VIIIa
ProUrokinase
X
Fibrinolysis
T-PA
Va
IIa
VIII
UreKinase
Plasminogen
V
Plasmin
Common
Pathway
XIIIa
Fibrinogen
Fibrin
Polymer
XIII
Fibrin Clot
+ Platelet Plug
Extrinsic
Pathway
(PT)
VII
Tissue
Factor
VIIa
X
Xa
II
Va
IIa
Common
Pathway
V
XIIIa
Fibrinigen
Fibrin
Polymer
XIII
Fibrin Clot
+ Platelet Plu
Factor VII
Biosynthesis: Liver, Vitamin K dependent
MW: 55,000 daltons
Plasma Concentration: 1 mg/L
In Vivo Half-Life: 5 hours
Pathology: Hypoproconvertinemia, autosomal recessive
Proconvertin,
Stable Factor
High
Molecular
Weight
Kininogen
Ca++
Phospholipid
(Platelet
Factor 3)
Factor
Xa
or
Factor
XIIa
or
Factor
IXa
Factor
VII
Factor
Xa
Factor
VIIa
Tissue
Factor
Ca++
Factor
VIIa
*Tissue Factor Pathway
Inhibitor
Factor X
Biosynthesis: Liver, Vitamin K dependent
MW: 55,000 daltons
Plasma Concentration: 5 mg/L
In Vivo Half-Life: 65 hours
Pathology: Stuart disease, autosomal recessive
Stuart-Prower Factor
Tissue Factor
Factor III,
Thromboplastin
Biosynthesis: Brain,
lung,
subendothelium
MW: 45,000 daltons
Ca++
Ca++
Tissue
Factor
Extrinsic
X-ase
Complex
Factor
VIIa
Factor X
or
Intrinsic
X-ase
Complex
Factor
VIIIa
Phospholipid
(Platelet
Factor 3)
Factor
IXa
Factor
Xa
Factor
Xa
Heparin
Antithrombin
III
Heparin
HMWK
Kallikrein
Prekallikrein
Kinins
XII
XIIa
XIa
Intrinsic
Pathway
(aPTT)
XI
IXa
IX
Xa
II
VIIIa
Va
IIa
X
VIII
V
Common
Pathway
XIIIa
Fibrinogen
Fibrin
Polymer
XIII
Fibrin Clot
+ Platelet Plug
Biosynthesis: Liver
MW: 80,000 daltons
Plasma Concentration: 29 mg/L
In Vivo Half-Life: 60 hours
Pathology: Hageman trait, autosomal recessive
Factor XII
Hageman Factor
Negatively
Charged
Activating
Surface
(e.g., kaolin,
ellagic acid Kallisilica)
krein
High
Molecular
Weight
Kininogen
Factor
XII
High Blood
Pressure
and
Inflammation
Factor XII
Fragments*
Kinins
Factor
XIIa
Factor
XIIa
HMWK
C1
Esterase
Inhibitor
High Molecular Weight
Kininogen (HMWK)
Fitzgerald Factor
MW: 120,000 daltons
Plasma Concentration: 70
mg/L
Pathology: Fitzgerald trait,
autosomal recessive
* FXIIf alter vascular permeability
Prekallikrein
Biosynthesis: Probably Liver
MW: 107,000 daltons
Plasma Concentration: 50 mg/L
Pathology: Fletcher trait, autosomal recessive
Fletcher Factor
Ca++
High
Molecular
Weight
Kininogen
Factor
XIIa
Prekallikrein
Kallikrein
Kallikrein
C1
Esterase
Inhibitor
Factor XI
Plasma Thromboplastin
Antecedent
Ca++
High
Molecular
Weight
Kininogen
Biosynthesis: Liver
MW: 158,000 daltons
Plasma Concentration: 4 mg/L
In Vivo Half-Life: 65 hours
Pathology: Hemophilia C, autosomal recessive
Factor
XIIa
Factor XI
Factor
XIa
Factor
XIa
a1Antitrypsin
Biosynthesis: Liver, Vitamin K dependent
MW: 57,000 daltons
Plasma Concentration: 4 mg/L
In Vivo Half-Life: 20 hours
Pathology: Hemophilia B, (Christmas disease) x-linked recessive
Factor IX
Christmas Factor
Ca++
Tissue
Factor
Factor
VIIa
or
Ca++
Factor
XIa
Factor IX
Factor
IXa
Antithrombin
III
Factor
IXa
Heparin
Heparin
Factor VIII
Antihemophilic Factor
vWF
von Willebrand Factor
Biosynthesis: Liver, endothelium; Factor VIII Related Antigen, megakaryocyte
MW(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
Factor
IIa
or
Factor
Xa
Factor
VIII
Factor
VIIIa
Inactive
Fragments
Activated
Protein C
Phospholipi
d
Ca++ (Platelet
Factor 3)
Protein C
Complex
Protein
S
Biosynthesis: Liver, Vitamin K dependent
MW: 70,000 daltons
Plasma Concentration: 100 mg/L
In Vivo Half-Life: 100 hours
Pathology: Hypoprothrombinemia, autosomal recessive
Factor II
Prothrombin
Ca++
Prothrombinase
Phospholipid
Complex
Factor
Va
(Platelet
Factor 3)
Factor
Xa
Activation
Fragments
Factor
II
Factor IIa
(Thrombi
n)
Factor
IIa
Heparin
Anti-*
thrombin Heparin
III
*or Heparin Cofactor
II
Factor V
Proaccelerin, Labile Factor
Biosynthesis: Liver, megakaryocytes
MW: 330,000 daltons
Plasma Concentration: 5-12 mg/L
In Vivo Half-Life: 25 hours
Pathology: Parahemophilia, autosomal recessive
Factor
IIa
Factor
V
Factor
Va
Inactive
Fragments
Activated
Protein
Ca++
C
Phospholipid Protein
S
(Platelet
Factor 3)
Protein C
Complex
Fibrinogen
Factor I
Biosynthesis: Liver
MW: 340,000 daltons
Plasma Concentration: 2500 mg/L
In Vivo Half-Life: 20 hours
Pathology: Afibrinogenemia, autosomal recessive. Dysfibrinogenemia,
autosomal dominant
CA+
Factor
IIa
Fibrinogen
Factor II
Fibrin
Polymer
Factor
IIa
Fibrinopeptid
eA
Procoagulant
Activation
Factor
IIa
Fibrin
Monomer
Plasmin
Plasmin
Fibrinopeptid
eB
Factor
Soluble XIIIa
Fibrin
Polyme
r
Plasmin
FDPs
Fibrinogen
Degradatio
n
Products
FDPs & XDPs
(Cross-linked DPs)
(e.g. D-dimers)
Factor
XIII
Factor XIII
Fibrin Stabilizing Factor
(FSF)
Biosynthesis: Megakaryocytes,
liver
MW: 320,000 daltons
Plasma Concentration: 10mg/L
In Vivo Half-Life: 12 days
Pathology: FSF deficiency,
autosomal recessive
Fibrin
(Factor
Ia) Activate
d
Platelet
s
Stable
Thrombus
(Clot)
Prothrombin Time
Factors
Thromboplastin
and Calcium
Patient’s
Plasma
I
II
V
VII
X
Activated Partial
Thromboplastin Time
Factors
Ca++
Phospholipid
and Activator
Patient’s
Plasma
I
II
V
VIII
IX
X
XI
XII
Quantitative Fibrinogen
60
1:4
0 1:3
0 1:2
0
30
High
concentration
of thrombin
10
6
1:1
0
1:5
3
1:10 dilution
patient’s
plasma
20
40 60 100
200 400 600
Fibrinogen in mg/dL
Heparin/AT-III Complex
Minimum Plasma Levels
Factor
I Fibrinogen
II
V
VII
VIII
Hemophilia A
von Willebrand
IX
X
XI
XII
Williams, W. J., Hematology, 1972
XIII
Minor
Spontaneous
Hemorrhage
Major
Trauma
or Surgery
50-100
10-15
5-15
5-10
5-10
15-20
25
10-15
5-10
5-15
10
1
100 mg/dL
20-40%
25%
10-20%
10-20%
25%
25%
20-25%
15-20%
15-25%
10%
5%
Vessels
Coagulation
Proteins
Platelets
Fibrinolysis/Inhibitors
Fibrinolysis
Activators: t-PA,u-PA, STK, XII, HMWK, PK
Plasminogen
Plasmin
Fibrinogen
Fibrin
Degradation Products
R.E.S.
Biosynthesis: Liver
MW: 90,000 daltons
Plasma Concentration: 120 mg/L
In Vivo Half-Life: 48 hours
Pathology: Plasminogen deficiency, autosomal dominant.
Dysplasminogenemia, autosomal recessive
Plasminogen
tPA
or
Urokinase
or (tissue
Kallikrein Plasminogen
Activator)
Plasminogen
Plasmin
Plasmin
a2 - Antiplasmin
HMWK Prekalli-
VII
Extrinsic
Pathway
(PT)
Kallikrein
krein
Kinins
XII
XIIa
Tissue
Factor
XIa
Intrinsic
Pathway
(aPTT)
XI
VIIa
IXa
IX
X
II
Xa
VIIIa
ProUrokinase
X
Fibrinolysis
T-PA
Va
IIa
VIII
UreKinase
Plasminogen
V
Plasmin
Common
Pathway
XIIIa
Fibrinogen
Fibrin
Polymer
XIII
Fibrin Clot
+ Platelet Plug
Antithrombin-III Inhibition
of Thrombin
Lysine Site
Thrombin, Antithrombin-III
and Heparin
Serine Site
Thrombin
(Active)
Antithrombin-III
(Nonactivated)
Heparin
Acidic Site
Arginine Site
Heparin
Inactivation of Thrombin
Thrombin
(Inhibited)
Antithrombin-III
(Complexed)
Antithrombin-III
Heparin Thrombin Complex
Antithrombin-III
Decreased Levels
1. Congenital
2. Acquired – decreased synthesis
3. Acquired – increased utilization
4. Drug-induced
Protein C
• Vitamin K-dependent plasma protein
• Inactivates Factors V and VIII
• Stimulates fibrinolysis
Biosynthesis: Liver, Vitamin K dependent
MW: 56,000 daltons
Plasma Concentration: 3-5 mg/L
In Vivo Half-Life: 6-7 hours
Pathology: Protein C deficiency, autosomal recessive (?)
Protein C
Thrombomodulin
Factor
IIa
Protein C
Activation
Peptide
Protein
C
Activated
Protein
C*
Activated
Protein C
* Requires Protein S for
functional activity
Protein C
Inhibitor
Deficiencies of Protein C
I. Congenital
Hereditary autosomal dominant
II. Acquired
A. DIC
B. Liver disease
C. During post-operative period
D. Anticoagulant therapy
Clinical Manifestations
• Superficial thrombophlebitis
• Venous thromboses in adolescents or
young adults
• Arterial thromboses rarely observed
• Skin necrosis during onset of oral
anticoagulant therapy
Protein S
• Cofactor for Protein C
• Vitamin K-dependent protein
• Enhances binding of Protein C to
phospholipid surfaces