The Physiology of coagulation

1
The Physiology of coagulation

• How to clot
• But not too much

2
Basis

• Blood flows through intact vessels
• Resting state is designed to keep blood flowing
• Arteries rapid flow. Injury requires a plug
• Rapid, localised, controlled.
• minimise blood flow compromise
• Veins slower, intermittent flow
• Systemic anticoagulant
• clot dissolving system

3

• Complex activating and inhibition system
• Five components
• Vessels
• Platelets
• Coagulation factors (clot forming)
• Coagulation inhibitors (clot controlling)
• Fibrinolysis (clot dissolving)

4
Haemostasis

• Vasoconstriction
• Platelets activated by thrombin form a platelet
  plug
• Fibrin mesh forms via activation of the
  coagulation system to strengthen the clot
• Clot dissolution via plasmin
• Normal blood flow past the clot

5
(No Transcript)
6
(No Transcript)
7
Platelet shape change

• Pseudopod formation
• Interact with adjacent platelets
• Contract later to consolidate the platelet plug
  in process of clot retraction

8
Platelet adhesion

• Platelet receptors (integrins)
• Glycoprotein Ib/IX
• Glycoprotein Ia/IIa
• Ligands interact with receptors
• Von Willebrand factor
• Large (high molecular weight) multimers
• collagen

9
(No Transcript)
10
Platelet release reaction

• Stimuli
• Adrenaline, collagen, ADP, thrombin
• Release of preformed active substances from
  granules
• ADP, serotonin, lysozyme,factor V, thrombospondin
  
• Activate the prostaglandin pathway
• Thromboxane A2 via cyclooxygenase
• Calcium release
• Glycoprotein IIb/II activation

11
Platelet
Phospholipase A2
Phospholipid
Arachadonic acid
Cyclooxygenase
Endoperoxidases
Thromboxane synthase
Thromboxane A2
Phosphodiesterase
Calcium flux
12
Platelet aggregation

• Platelet receptor
• Glycoprotein IIb/IIIa
• Ligands
• Von Willebrand factor
• Fibrinogen
• IRREVERSIBLE aggregation -gt Plug

13
(No Transcript)
14
(No Transcript)
15
Coagulation forms fibrin mesh

• Biological amplification system which converts
  soluble fibrinogen to an insoluble fibrin
  meshwork which coverts the primary platelet plug
  to a firm, definitive stable clot.
• Required local concentration of clotting factors
  at site of injury
• Surface mediated reactions on exposed collagen,
  platelet phospholipid or tissue factor

16
General concepts

• Coagulation factors act as proteases when
  activated (serine proteases)
• Zymogens (inactive eg fibrinogen) converted to
  enzymes/proteins by limited proteolysis
• Complex formation requiring calcium,phospholipid
  surface, cofactors
• Thrombin converts fibrinogen to fibrin monomer
• Fibrin monomer crosslinked to fibrin
• Forms "glue" for platelet plug

17
Cascade effect -gt amplification
Fibrin mesh
2x108mol
1 mol
18
(No Transcript)
19
Coagulation cascade
Intrinsic pathway
XII
XI
Extrinsic pathway
IX
VII
APTT
VIII
X
PT
thrombin
Prothrombin (II)
V, Ca, P/L
fibrin
fibrinogen
XIII
STABILISED FIBRIN
20
INITIATION
IIa (Thrombin)
X
Xa
II (Prothrombin)
21
AMPLIFICATION
22
Fibrinogen -gt fibrin

• Thrombin cleaves fibrinogen
• Fibrinopeptide release
• Fibrin monomers
• Spontaneously link to form a loose polymer
• Fibrin meshwork is stabilised by factor XIIIa
  (activated by thrombin and calcium)

23
(No Transcript)
24
Inhibitors ANTI-coagulants

• Antithrombin III
• Directly inactivates serine proteases
• Thrombin and Xa. Also IXa and Xia
• Potentiated by heparin
• Protein C
• Inhibits (cleaves) the cofactors VIIIa and Va
• Significantly decreases the rate of clot
  formation
• Needs to be activated

25

• Protein S
• Enhances activity of protein C
• Thrombomodulin
• Activated by thrombin
• Binds to thrombin to alter its conformation
• Complex activates protein C
• Tissue pathway factor inhibitor
• Inhibits FVIIa-tissue factor complex

26
Anticoagulants

• Too little or ineffective
• Extensive clot
• Too much
• Bleeding
• Therapeutics
• Heparin
• Activated protein C
• TPFI inhibitor

27
Fibrinolysis

• Prevents excessive fibrin deposition
• Allows closely coupled with fibrin formation
• Localised surface bound phenomenon that is
  catalysed by fibrin formation

28
Components fibrinolysis

• Plasminogen -gt plasmin
• Plasminogen activators
• Inactivators of plasminogen
• Inhibitors of plasmin

29
(No Transcript)
30
Effect of plasmin

• Lyses factor V and VIII
• Proteolysis of fibrinogen
• Removes small peptides
• Degradation of fibrin
• Fibrin degradation products (FDP)s
• D-Dimers

31
(No Transcript)
32
Blood Vessel endothelium

• Active
• Haemostasis factors
• Von Willebrand factor
• Tissue factor expressed after injury
• Anticoagulant factors
• ATIII, protein S, thrombomodulin
• Fibrinolysis
• Tissue plasminogen activator

33
(No Transcript)
34
Haemostatic response

• Vasoconstriction
• Initial slowing of blood flow to injured area
• Smooth muscle in arterioles
• Vasoactive substances
• Platelet primary plug formation
• Collagen/VWF
• Glycoprotein Ib/IX and IIb/IIIa
• Aggregation with arachadonic acid pathway

35
Haemostatic response

• Stabilsation of the platlelet plug with fibrin
• Tissue factor activation of coagulation cascade
• Thrombin burst
• Formation of fibrin meshwork

36
Haemostasis reaction

• Regulation of fibrin clot
• Activation of fibrinolysis
• Tissue plasminogen activator
• Plasmin -gt FDPs

37
A test tube is not a person

• Coagulation in vivo
• Temperature
• pH
• Calcium
• That is hypothermic , acidotic, hypocalcaemic
  patients dont clot

38
(No Transcript)
39
(No Transcript)
40
(No Transcript)
41
(No Transcript)
42
(No Transcript)
43
(No Transcript)