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Hemostasis
http://upload.wikimedia.org/wikipedia/commons/e/e6/Bleeding_finger.jpg -
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Hemostasis
a body mechanism
to stop traumatic bleeding
to prevent spontaneous bleeding
to keep the fluidity of blood
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Vascular injury
tissue thromboplastin platelet adherent vaso constriction
F XII activation ADP
primary platelet aggregation
PF3 ADP5 OH tryptaminTxA2
secondary platelet aggregation(semi permeable platelet plug)
fibrin
non permeable platelet plug
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Reactions in hemostatic process
Vascular reaction
primary hemostatic
barrierCellular reaction
Biochemical reaction / secondary
hemostatic barrier
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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 (PGI2)
Thrombomodulin (PC activation)
Glycosaminoglycan (heparan sulphate, dermatan sulphate)
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Platelet
Originated from cytoplasm of megakariocyte(fragmentation)
Morphology : discoid, biconvex, 2 4 m
Cytoplasm contains: a-granule (PF4, b-thromboglobulin, platelet derived growth
factor, vWF, fibrinogen, F V)
Dense granule (Ca, ADP, ATP)
Membrane: phospholipid bilayer, glycoprotein(receptor)
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Megakaryoblast Megakaryocytes Platelets
1/3 of platelets: stored in spleen
2/3 of plateletes: blood circulationhalf-lime 3-4 days
15% use daily for haemostasis
normal platelet count 140-360 x 109/l
The Platelets
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Morphology of platelet
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The role of platelet in hemostasis
Platelet plug formation: Platelet adherent (need von Willebrand Factor)
Platelet aggregation stimulated by ADP, thrombin,thromboxan A2, epinephrine, collagen
Platelet release reaction (from agranule and dense granule) Stabilization of the plug : platelet factor 3 (flip flop
of membrane phospholipid)
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Platelet Function
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phospholipid
Arachidonic acid
PGG2, PGH2
Thromboxan A2
Phospholipase A2, C
cyclooxygenase
Thromboxansynthetase
Aspirin
Prostacyclin
PGI2synthetase
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Coagulation Factors
Factor I Fibrinogen precursor of fibrin
Factor II Prothrombin serine protease
Factor III Tissue thrombo initiate extrinsic path.
plastinFactor IV Calsium ion bridge between
Gla - phospholipid
Factor V Proaccelerin Cofactor of XaFactor VII Proconvertin serine protease
Factor VIII Anti hemophilic f. Cofactor of IXa
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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
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Vitamin K
Vit. K is required for carboxylation of glutamic acid 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)
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ResidueGlutamic acid
(GLU)
Precursor ofII, VII, IX, X
ProthrombinVII, IX, X
ResiduegCarboxy glutamat
(GLA)
carboxylase
Vitamin KH2
Vitamin Kepoxide
Oral
Anticoagulant
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Negative surface Tissue thromboplastinKal. PKHMWK
XII XIIa
XI XIa VIIa VII
IX IXaCa++
Pf3
VIII VIIIa
X XaCa++
Pf3V Va Fibrinogen
Prothrombin ThrombinFibrin monomer
Fibrin polimerXIII XIIIa
Stabilized fibrin
Ca++
FPA
FPB+
F1.2
+
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Mechanism of coagulation factor activation
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Homeostatic mechanismLocal: fibrin, blood flow
Humoral:
- Antithrombin
- Protein C- Protein S
- Heparin cofactor II
- TFPICellular : liver cell, RES
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Antithrombin
Synthesized in the liver
Function : neutralize thrombin and other serineprotease (XIIa, XIa, Xa, IXa, VIIa,
Kallikrein,plasmin) Heparin cofactor
Activities enhanced by heparin
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Function of antithrombin
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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.
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Protein C pathway
ssue actor pat way n tor
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ssue actor pat way n tor(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
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Mechanism of action of TFPI
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Fibrinolytic system
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Fibrinolytic system
Fibrinolysis is a physiologic response tothe deposition of intra or extra vascular
fibrin
Function : to destroy fibrin by enzymaticprocess
Consist of :
Plasminogen
Plasminogen Activator
Inhibitor
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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
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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
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Inhibitor of fibrinolysis system
Antiplasmin:
2plasmin inhibitor
2macroglobulin antithrombin
1antitrypsin
TAFI Transamin
Plasminogen activatorinhibitor
PAI-1
PAI-2
PAI-3 (?)
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Coagulation and Fibrinolytic cascade
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Plasminogen Free plasminogenin clot
PAI
Plasminogen activator
Plasmin Free plasmin antiplasminin clot
Fibrin FDP Fibrinogen FDPD dimer + F V, F VIII D dimer -
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Contact activation
XIa
IXa + VIII APC
TM
TF-VIIa Xa+V IIa Fibrin
Fibrinolysis
TFPI TM
TAFI
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