White cells eg neutrophils
Red cells
Nerves
Endothelium
Platelets
Smooth muscle
Platelet adhesion, aggregation, release
Coagulation → thrombin
Local vasoconstriction
Balance of stimulatory/inhibitory mediators
Haemostasis trigger = tissue damage
Thrombosis trigger = plaque rupture?
Interactions between :
•platelets
•coagulation cascade
•endothelial cells
•vascular smooth muscle (neuronal control too)
Thrombosis and haemostasis
Resting platelet
Activated platelet
Starts within seconds, finished within a couple of minutes
Adhere to eg vessel wall
Change shape – from disc to spiny sphere
Expose fibrinogen receptors at their surface
Expose PF3 at their surface
Synthesise lipid-derived mediators (TXA2, PGD2, PAF)
Synthesise nitric oxide (NO)
Release the contents of their dense granules (5-HT, ADP,
ATP)
Release the contents of their alpha granules (proteins –
including PF4, fibrinogen, vWF, PDGF)
What do platelets do when they are activated?
Blood clotting
Thrombin
Release of soluble
mediators
Exposure of PF3
(procoagulant
phospholipids)
Fibrinogen + Ca2+
ADP or other
aggregating agents
PLATELET RESPONSES:
Shape change, aggregation, release
Release of α
granule contents
Binds to activated platelets
Ca2+
Fibrinogen
II Prothrombin
XIIIa
Blood clot
Ca2+
XIII
Stabilised fibrin
Fibrin
IIa Thrombin
Ca2+, PF3
Xa
Ca2+, PF3
Ca2+, PF3
X
Extrinsic pathway
(tissue damage)
Intrinsic pathway
(in vitro contact)
And by small molecules:
•ADP/ATP – from damaged cells and platelets
•PGH2/TXA2 – from platelets
•PAF – from platelets
•5-HT – from platelets
•adrenaline/NA - circulating hormones
Platelets are stimulated by proteins:
•collagen - subendothelial surface
•thrombin – coagulation cascade
Platelet activation involves an increase in cytoplasmic Ca2+
Platelet activation
Platelets are inhibited by :
•PGI2 – from endothelium
•PGD2 – from platelets
•adenosine – released by hypoxic cells,
formed during ADP/ATP degradation
•NO – from platelets and endothelium
Platelet inhibition involves an increase in
cytoplasmic cyclic nucleotides (cAMP or cGMP)
Platelet inhibition
As a general rule:
• things that activate platelets also constrict blood vessels
• things that inhibit platelets also relax blood vessels
Inhibitory mediators:
•NO - synthesised
•PGD2 - synthesised
Stimulatory mediators:
•ADP/ATP – stored in vesicles
•5-HT – stored in vesicles
•PGH2/TXA2 - synthesised
•PAF - synthesised
Platelets release soluble compounds that affect nearby cells
Platelet mediators
If the endothelium is damaged aggregation and
vasoconstriction will dominate - THROMBOSIS
Healthy intact endothelium will respond by releasing factors
that inhibit aggregation and cause vasodilation – PGI2 and
NO
The endothelium is important in determining whether or not
platelet aggregation will spread or be reversed
Interactions between platelets and the vessel wall determine
the final outcome of an initial small aggregation
Platelet-vessel wall interactions
PGI2 + NO
PAF
ADP
5-HT
NO
AGGREGATION
VASODILATION
Thrombin
PGH2/TXA2
PGH2/TXA2
PAF
5-HT
ADP
Collagen
Thrombin
Platelet factor 3
Vascular
smooth muscle
Endothelium
Adenosine
PGI2
Healthy endothelium:
platelets will not
aggregate, blood vessel
will relax
Thrombin
PAF
ADP
5-HT
AGGREGATION
Platelet factor 3
CONTRACTION
PGH2/TXA2
PGH2/TXA2
PAF
5-HT
ADP
Collagen
Thrombin
NO
Vascular
smooth muscle
Damaged endothelium:
platelets will
aggregate, blood vessel
will contract