1. Nerves Smooth muscle Endothelium Platelets White cells eg neutrophils Red cells

2. 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)

3. Resting platelet Activated platelet

4. 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 (TXA 2, PGD 2, 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

5. PLATELET RESPONSES: Shape change, aggregation, release ADP or other aggregating agents Fibrinogen + Ca 2+ Release of soluble mediators Exposure of PF3 (procoagulant phospholipids) Blood clotting Thrombin Release of α granule contents

6. Intrinsic pathway (in vitro contact) Extrinsic pathway (tissue damage) X Xa II ProthrombinIIa Thrombin FibrinogenFibrin Blood clot Ca 2+, PF3 XIIIa XIII Stabilised fibrin Ca 2+ Binds to activated platelets Ca 2+

7. Platelet activation Platelet activation involves an increase in cytoplasmic Ca 2+ Platelets are stimulated by proteins: collagen - subendothelial surface thrombin – coagulation cascade And by small molecules: ADP/ATP – from damaged cells and platelets PGH 2 /TXA 2 – from platelets PAF – from platelets 5-HT – from platelets adrenaline/NA - circulating hormones

8. Platelet inhibition Platelet inhibition involves an increase in cytoplasmic cyclic nucleotides (cAMP or cGMP) Platelets are inhibited by : PGI 2 – from endothelium PGD 2 – from platelets adenosine – released by hypoxic cells, formed during ADP/ATP degradation NO – from platelets and endothelium

9. Platelet mediators Platelets release soluble compounds that affect nearby cells Stimulatory mediators: ADP/ATP – stored in vesicles 5-HT – stored in vesicles PGH 2 /TXA 2 - synthesised PAF - synthesised Inhibitory mediators: NO - synthesised PGD 2 - synthesised As a general rule: things that activate platelets also constrict blood vessels things that inhibit platelets also relax blood vessels

10. 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 – PGI 2 and NO If the endothelium is damaged aggregation and vasoconstriction will dominate - THROMBOSIS

11. AGGREGATION ADP 5-HT NO PAF ADP 5-HT PGH 2 /TXA 2 Thrombin Collagen Adenosine PGI 2 Platelet factor 3 Thrombin PGI 2 + NO Endothelium Vascular smooth muscle PGH 2 /TXA 2 VASODILATION PAF Healthy endothelium: platelets will not aggregate, blood vessel will relax

12. AGGREGATION ADP 5-HT NO PAF ADP 5-HT PAF PGH 2 /TXA 2 Thrombin Collagen Thrombin Vascular smooth muscle PGH 2 /TXA 2 CONTRACTION Platelet factor 3 Damaged endothelium: platelets will aggregate, blood vessel will contract