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Hemostasis

Hemostasis
a body mechanism
to stop traumatic bleeding
to prevent spontaneous bleeding
to keep the fluidity of blood
Vascular injury


tissue thromboplastin platelet adherent vaso constriction

F XII activation ADP


primary platelet aggregation

PF3 ADP
5 OH tryptamin
TxA2

secondary platelet aggregation
(semi permeable platelet plug)
fibrin


non permeable platelet plug
Reactions in hemostatic process
Vascular reaction
primary hemostatic
barrier
Cellular reaction
Biochemical reaction / secondary
hemostatic barrier
The role of vascular in hemostasis
vaso constriction
Stimulates coagulation factors and platelets
Substances synthesized by endothelial cells:
von Willebrand factor
tissue plasminogen activator (t-PA)
plasminogen activator inhibitor -1 (PAI-1)
prostacyclin (PGI
2
)
Thrombomodulin (PC activation)
Glycosaminoglycan (heparan sulphate, dermatan sulphate)
Platelet
Originated from cytoplasm of megakariocyte
(fragmentation)
Morphology : discoid, biconvex, 2 4 m
Cytoplasm contains:
a-granule (PF
4
, b-thromboglobulin, platelet derived growth
factor, vWF, fibrinogen, F V)
Dense granule (Ca, ADP, ATP)
Membrane: phospholipid bilayer, glycoprotein
(receptor)

Megakaryoblast Megakaryocytes Platelets
1/3 of platelets: stored in spleen

2/3 of plateletes: blood circulation
half-lime 3-4 days
15% use daily for haemostasis
normal platelet count 140-360 x 10
9
/l
The Platelets
Morphology of platelet
The role of platelet in hemostasis
Platelet plug formation:
Platelet adherent (need von Willebrand Factor)
Platelet aggregation stimulated by ADP, thrombin,
thromboxan A
2
, epinephrine, collagen
Platelet release reaction (from a granule and dense granule)
Stabilization of the plug : platelet factor 3 (flip flop
of membrane phospholipid)
Platelet Function
phospholipid
Arachidonic acid
PGG2, PGH2
Thromboxan A2
Phospholipase A2, C
cyclooxygenase
Thromboxan
synthetase
Aspirin
Prostacyclin
PGI2
synthetase
Coagulation Factors
Factor I Fibrinogen precursor of fibrin
Factor II Prothrombin serine protease
Factor III Tissue thrombo initiate extrinsic path.
plastin
Factor IV Calsium ion bridge between
Gla - phospholipid
Factor V Proaccelerin Cofactor of Xa
Factor VII Proconvertin serine protease
Factor VIII Anti hemophilic f. Cofactor of IXa
Coagulation factors (cont)
Factor IX Christmas factor serine protease
Factor X Stuart Prower factor serine
protease
Factor XI Antihemophilic C serine protease
Factor XII Hageman factor serine
protease
Factor XIII Fibrin stabilizing f.
transglutaminase
Prekallikrein Fletcher factor serine
protease
HMW kininogen Fitzgerald factor cofactor of
Kall.

Vitamin K
Vit. K is required for carboxylation of glutamic acid
g carboxy glutamate
Vitamin K dependent protein : prothrombin, VII,
IX, X, protein C, protein S, protein Z
Deficiency of vit. K PIVKA (protein induced by
vitamin K absence or antagonist)
Residue
Glutamic acid
(GLU)
Precursor of
II, VII, IX, X
Prothrombin
VII, IX, X
Residue
g Carboxy glutamat
(GLA)
carboxylase
Vitamin KH2
Vitamin K
epoxide
Oral
Anticoagulant

Negative surface Tissue thromboplastin
Kal. PK
HMWK
XII XIIa

XI XIa VIIa VII

IX IXa
Ca
++
Pf
3


VIII VIIIa

X Xa
Ca
++
Pf
3



V Va Fibrinogen

Prothrombin Thrombin
Fibrin monomer

Fibrin polimer
XIII XIIIa

Stabilized fibrin
Ca
++
FPA
FPB
+
F1.2
+

Mechanism of coagulation factor activation
Homeostatic mechanism
Local: fibrin, blood flow
Humoral:
- Antithrombin
- Protein C
- Protein S
- Heparin cofactor II
- TFPI
Cellular : liver cell, RES
Antithrombin
Synthesized in the liver
Function : neutralize thrombin and other serine
protease (XIIa, XIa, Xa, IXa, VIIa,
Kallikrein,plasmin)
Heparin cofactor
Activities enhanced by heparin
Function of antithrombin
Protein C and protein S
Both are vitamin K dependent protein
Thrombin with thrombomodulin as cofactor
activates Protein C activated Protein C (APC)
APC with Protein S as cofactor inactivates F Va and F
VIIIa.
Protein C pathway

Tissue factor pathway inhibitor
(TFPI)
Function : inhibit F Xa and F VIIa
Mechanism of action:
First F Xa + TFPI F Xa-TFPI complex
F Xa-TFPI complex + F VIIa-TF complex
quartener complexed
Mechanism of action of TFPI
Fibrinolytic system
Fibrinolytic system
Fibrinolysis is a physiologic response to
the deposition of intra or extra vascular
fibrin
Function : to destroy fibrin by enzymatic
process
Consist of :
Plasminogen
Plasminogen Activator
Inhibitor
Fibrinolytic system
Plasmin : proteolytic enzyme, substrates : fibrin,
fibrinogen, V, VIII, hormon, complement
PLasminogen : proenzyme of plasmin, found in
plasma and other body fluid
Plasminogen activator
Inhibitor
Plasminogen activator
Physiologic plasminogen activators:
Tissue-type plasminogen activator (t-PA)
Urinary- type plasminogen activator (u-
PA)
Contact-phase dependent activators: F XIIa,
Kallikrein
Exogen:
Streptokinase (SK)
Staphylokinase (SAK)
Vampire bat plasminogen activator

Inhibitor of fibrinolysis system
Antiplasmin:
a
2
plasmin inhibitor
a
2
macroglobulin
antithrombin
a
1
antitrypsin
TAFI
Transamin
Plasminogen activator
inhibitor
PAI-1
PAI-2
PAI-3 (?)


Coagulation and Fibrinolytic cascade

Plasminogen Free plasminogen
in clot

PAI

Plasminogen activator



Plasmin Free plasmin antiplasmin
in clot



Fibrin FDP Fibrinogen FDP
D dimer + F V, F VIII D dimer -

Contact activation



XIa

IXa + VIII APC

TM

TF-VIIa Xa+V IIa Fibrin

Fibrinolysis

TFPI TM
TAFI