onkologi hem

8/12/2019 onkologi hem

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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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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


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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