A.1.2. Temporary platelet plug formation

3 stages:

1. Platelet adhesion
2. Platelet activation
3. Platelet aggregation

A.1.2.1. Platelet adhesion

When blood vessel injured
--> Platelet adhere to exposed collagen and vWF via receptors on membrane
--> Binding activates platelets

Adhesion mechanism

2 mechanisms:

• Adhesion to collagen is facilitated by glycoprotein Ia (on the membrane)
• Adhesion to vessel wall vWF is by glycoprotein Ib-IX complex (on the membrane)
  * vWF = von Willebrand factor

A.1.2.2. Platelet activation

Platelet activation can be induced by

• Adhesion to proteins such as collagen, soluble agonist (epinephrine, ADP, serotonin, thrombin)
• Cell contact during platelet aggregation
• Platelet-activating factor (PAF)
  * A cytokine secreted by neutrophils, monocytes, and platelets
  * Also has inflammatory activity
  * Acts via G protein-coupled receptor to increase production of arachidonic acid derivatives (including thromboxane A2)

Platelet activation is inhibited by

• Prostacyclin (PGI2)

Activation results in

1. Activation of membrane phospholipase A2 and phospholipase C
   --> Various biochemical reactions
   * e.g. Production of thromboxane A2
2. Reorganisation of cytoskeleton
   --> Platelet transforms from a disc to a sphere with long pseudopods spreading onto subendothelial matrix [PK1:p248]
3. Release of granules
4. Exposure of platelet phospholipids
   * aka PF3
   * Provides a surface for assembly of 10ase (i.e. 8a/9a complex) and prothrombinase (i.e. 10a/5a)
   * [HH26:p601]

NB:

• Thromboxane A2
  --> Lowers platelet cAMP
  --> Initiate granule release
  * Also promote vasoconstriction and platelet aggregation
  * [PK1:p248]
  * Also see Endothelium-related vasoactive substances
  * Cyclooxygenase which catalyses the producion of TXA2 is blocked by aspirin

Release of granules

• Dense granule is released within 30 seconds
  * Serotonin, ADP
  --> Reinforce platelet activation
• Alpha-granule is released after 30 seconds
  * vWF, fibrinogen, PDGF, etc
  --> Reinforce and mediate platelet aggregation and adhesion

A.1.2.3. Platelet aggregation

Platelet aggregation occurs when platelets encounter:

• Released thromboxane A2
  --> Platelet aggregation at the site of vascular injury
• Released ADP
  --> Act on ADP receptors on platelet membrane
  --> Promote platelet to platelet aggregation, and release of more ADP and thromboxane A2
  * i.e. Positive feedback
• Thrombin
  * Also a potent platelet granule release inducer

NB:

• Platelet-to-platelet aggregation occurs when
  * Fibrinogen or vWF binds to the GPIIb-IIIa complex on platelets
  --> Platelets linked to each other via fibrinogen or vWF

Other notes

Thrombin

• During platelet plug formation, minute amount of thrombin is produced by tissue factor
  --> Exposes platelet factor 3 (a negatively charged phospholipid)
  * PF3 provides a surface on which vitamin K dependent factors and Ca2+ bind
  * PF3 = platelet phospholipid
• Very important because of its role in
  * Enhancing platelet adhesion
  * Activating platelets
  * Activating factor 5, 8, 11