Nerves
Smooth muscle
Red cells
Platelets
White cells eg neutrophils
Endothelium
Thrombosis and haemostasis
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)
Resting platelet
Activated platelet
What do platelets do when they are activated?
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)
Starts within seconds, finished within a couple of minutes
PLATELET RESPONSES:
Shape change, aggregation, release
ADP or other
aggregating agents
Fibrinogen + Ca2+
Exposure of PF3
(procoagulant
phospholipids)
Thrombin
Blood clotting
Release of soluble
mediators
Release of α
granule contents
Intrinsic pathway
(in vitro contact)
Extrinsic pathway
(tissue damage)
Ca2+, PF3
Ca2+, PF3
X
Xa
Ca2+, PF3
II Prothrombin
IIa Thrombin
XIII
Ca2+
Fibrinogen
Fibrin
Ca2+
XIIIa
Stabilised fibrin
Binds to activated platelets
Blood clot
Platelet activation
Platelet activation involves an increase in cytoplasmic Ca2+
Platelets are stimulated by proteins:
•collagen - subendothelial surface
•thrombin – coagulation cascade
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
Platelet inhibition
Platelet inhibition involves an increase in
cytoplasmic cyclic nucleotides (cAMP or cGMP)
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 mediators
Platelets release soluble compounds that affect nearby cells
Stimulatory mediators:
•ADP/ATP – stored in vesicles
•5-HT – stored in vesicles
•PGH2/TXA2 - synthesised
•PAF - synthesised
Inhibitory mediators:
•NO - synthesised
•PGD2 - synthesised
As a general rule:
• things that activate platelets also constrict blood vessels
• things that inhibit platelets also relax blood vessels
Platelet-vessel wall interactions
Interactions between platelets and the vessel wall determine
the final outcome of an initial small aggregation
The endothelium is important in determining whether or not
platelet aggregation will spread or be reversed
Healthy intact endothelium will respond by releasing factors
that inhibit aggregation and cause vasodilation – PGI2 and
NO
If the endothelium is damaged aggregation and
vasoconstriction will dominate - THROMBOSIS
Thrombin
Healthy endothelium:
platelets will not
aggregate, blood vessel
will relax
Platelet factor 3
Collagen
ADP
PGI2
5-HT
AGGREGATION
PAF
Adenosine
PGH2/TXA2
PGH2/TXA2
Thrombin
NO
PAF
ADP
5-HT
PGI2 + NO
VASODILATION
Endothelium
Vascular
smooth muscle
Thrombin
Damaged endothelium:
platelets will
aggregate, blood vessel
will contract
Platelet factor 3
Collagen
ADP
5-HT
AGGREGATION
PAF
PGH2/TXA2
PGH2/TXA2
Thrombin
NO
PAF
CONTRACTION
ADP
5-HT
Vascular
smooth muscle