Mechanism of
Haemostasis &
Coagulation
DR. Khaled Khalil
At the end of the session the students should be able
to:
 Define hemostasis and enumerate the steps involved
in it.
Explain the mechanism of blood coagulation
 Discuss the anticoagulant mechanism of the body
 Identify the natural and synthetic anticoagulants
Guyton and Hall “Textbook of Medical Physiology”12thed (pg454460)
Haemostasis
Means: stoppage of bleeding when a small blood
vessel is injured
1. Local vascular spasm
2. Platelet plug formation
3. Blood clot formation
4. Fibrinolysis and fibrosis of the blood clot
A) Local vascular spasm
Immediately after the blood vessel is injured by the following
mechanisms:
1.
Nervous reflexes initiated by pain from traumatized blood vessel.
2.
Local myogenic contraction of smooth muscles due to direct
trauma, the more the traumatized the vessel the greater the
degree of spasm
3.
Humoral: through chemical substances released from the site of
injury (serotonin,TxA2, adrenaline,….)
Vascular spasm reduce blood flow to the injured BV
B) Platelet Plug Formation
• Upon damage to blood vessel endothelium (which exposes subendothelial
collagen) platelets:
1) Platelet adhesion: With the help of von Willebrand factor (VWF) adhere to
collagen through platelets membrane glycoprotein (Ib) and initial release
reactions (ADP, TxA2, serotonin)
2) Platelet activation: stimulated by ADP and thromboxane A2. Activated platelets
swell, develop pseudopodia, sticky and discharge their granules (ADP,
serotonin, TxA2, catecholamines, vWF, fibrinogen,…..)
3) Platelet aggregation: Release serotonin and ADP, attract more and more
platelets forming a mass of aggregated platelets (fibrinogen & Gp IIb/IIIa)
(platelet cohesion).
4) Formation of a platelet plug large enough to close a small rent in the BV wall.
Platelet plug initially is loose then become firm by contraction of the platelet
contractile proteins and by fibrin threads
2- Platelet Plug Formation
• Platelets adhesion is potentiated by vWF which is
plasma protein
Platelet Plug Formation
1) Aspirin inhibit TxA2 synthesis, so inhibit platelet
activation and aggregation
2) Activated platelet expose the platelet membrane
phospholipids (PF3) which is essential for blood
coagulation.
3) Normally there is thousands of minute rupture in
small BV (capillaries), that closed by platelet plug
formation (purpura)
C) Blood Colt formation
Coagulation (Clotting) Factors
Most of them are plasma
proteins (β globulin)
formed in the liver
Vitamin K-dependent
clotting factors are:
II, VII, IX, X
Most of them are present
as proenzymes
(inactive)
Once activated, it
induces a cascade
reaction
C) Blood Coagulation
• The third mechanism for hemostasis. (begin 20 sec - 2
m) (within 3- 6 m blood clot is formed)
• A series of reactions in which blood is transformed
from a liquid to a gel
• The main three steps of this series of reactions are:
1) Formation of Prothrombin activator complex: through
intrinsic and extrinsic pathways
2) Convertion of Prothrombin into thrombin
3) Thrombin catalyzes the convertion of fibrinogen into a fibrin
threads
1) Prothrombin activator complex
Formation of prothrombin activator occur by 2
pathways:
I) Extrinsic pathway: initiated by substance outside the blood
(tissue thromboplastin factor III) released due to trauma.
2) Intrinsic pathway: initiated by substances all present in
the plasma (factor XII).
There is cooperation between the 2 pathways in the
process of blood coagulation.
Coagulation Phase 1:
Two Pathways to Prothrombin Activator
• May be initiated by either the intrinsic or extrinsic
pathway
– Triggered by tissue-damaging events
– Each pathway cascades toward factor X
• Once factor X has been activated, it complexes with
Ca2+ ions, PF3, and factor V to form prothrombin
activator
A) Extrinsic pathway
Tissue thromboplastin (factor III) released from damaged tissue
and vascular wall (consist of lipoprotein & phospholipids)
1) Factor III activate factor VII to VIIa & form a complex with it.
2) Factor III/VIIa complex in the presence of Ca2+ activate factor X into Xa
3) Xa with factor V, PF3 (platelet phospholipid) and Ca2+ form the
prothrombin activator enzyme complex
4) Prothrombin activator act on prothrombin converting it thrombin
which then act on fibrinogen converting it to fibrin monomer
B) Intrinsic pathway
Exposure of the blood to damaged endothelium & rough subendothelial
collagen or contact with water wettable surface (glass) initiate the
activation of the intrinsic pathway (slow & terminates in 3 – 6 m) occur in
the following steps:
1) Contact activation of factor XII into XIIa
2) XIIa activate factor XI into active XIa
3) XIa activate factor IX into active IXa
4) IXa in the presence of factor VIII and Ca2+ and PF3 activate factor X into Xa
5) Xa with factor V, PF3 (platelet phospholipid) and Ca2+ form the prothrombin
activator enzyme complex
Prothrombin activator act on prothrombin converting it to
thrombin which then act on fibrinogen converting it to fibrin
monomer
blood Colt formation
Coagulation Phase 3:
Common Pathways to the Fibrin Mesh
Thrombin catalyzes the conversion of fibrinogen into fibrin
monomer that polymerized into fibrin threads.
Insoluble fibrin threads entrapping blood cells, platelets
and plasma forming loose blood clot
• Fibrin causes plasma to become a gel-like trap
• Fibrin in the presence of calcium ions & active
factor XIII that:
– Cross-links fibrin
– Strengthens and stabilizes the clot
Role of Ca+2 in blood clotting
Ca+2 required for acceleration of most of blood clotting
reactions
1. Absence of Ca2+ prevent blood clotting by the 2
pathways.
2. Citrate and oxalate salts (Ca2+ precipitating agents)
can be used as in vitro anticoagulants.
Clot Retraction and Repair
Clot retraction – stabilization of the clot by
squeezing serum from the fibrin strands
Repair of BV wall
– Platelet-derived growth factor (PDGF) stimulates
rebuilding of blood vessel wall, Fibroblasts form a
connective tissue patch
– Stimulated by vascular endothelial growth factor (VEGF),
endothelial cells multiply and restore the endothelial lining
Natural Anti-Clotting Mechanisms;
A- Endothelial Factors
• Healthy smooth endothelium will not provide
surface for platelets adhesion (NO & PGI2)
• Glycocalyx on endothelial surface is repellent for
platelets & clotting factors
• Thrombomodulin; protein bound to endothelial
membrane. It has anticoagulant effect via:
 Binding thrombin
 Thrombomodulin-thrombin complex activates Protein
C which inactivates factors V & VIII
B) Blood factors: (natural anti-clotting)
1) Continuous blood flowing:
– prevent contact activation of platelet & clotting factors
2) Fibrin formed during clot formation:
– adsorb 85% of thrombin & localize it action to the site of clot formation
prevent the extension of the clot
3) Antithrombin III:
– a plasma protein secreted by the liver
– bind to & inactivate thrombin &
– bind to & inactivate other active clotting factors (9, 10, 11, 12)
– Its action is markedly enhanced by heparin
4) Heparin:
– Sulphated polysaccharide (glucosaminoglycan)
– (secreted by mast cells & basophils)
– prevent blood clotting through increase the activity of antithrombin III
1000 times &
– stimulate fibrinolysis
B) Blood factors: (natural anti-clotting)
5) Protein C & protein S:
– Plasma proteins secreted by the liver & require vit K
– activated by thrombomodulin-thrombin complex & then inactive
clotting factors (V & VIII) in the presence of protein S &
– activate fibrinolysis by its binding to t-PA inhibitors
6) α1 antitrypsin & α2 macroglobulin: hydrolyze & inactivate thrombin
and many other clotting factors
7) Fibrinolytic system: dissolve & breakdown many small thrombi formed
in small BV & prevent their extension