Pharmacology of Anti-Platelet Drugs

• What are platelets?

  Anuclear blood cells

  Biconvex (smartie shape)

  1-3 µm in diameter

  Formed from megakaryocytes
• What is the lifespan of platlets?

  5 - 10 days
• Fill in the blanks

  A) RBC

  B) WBC

  C) Platelet

  
• Fill in the blanks

  A) alpha granules

  B) dense granule

  C) mitochondria

  
• Difference between haemostasis & thrombosis.

  Haemostasis

  • platelets & coagulation
  • stops bleeding/blood loss
  • activated following injury (normal resopnse)
  • maintains vascular integrity

  Thrombosis

  • arterial or venous
  • obstructs blood vessels
  • pathological activation (abnormal response)
• What are the 2 types of thrombosis?

  Arterial

  • tends to be related to platelets
  • MI, thrombotic stroke
  • TREATMENT: aspirin & anti-platelet drugs

  Venous

  • tends to be related to coagulation
  • DVT
  • TREATMENT: warfarin, heparin, DOACs
• What is the clinical importance of platelets?

  Inappropriate activation of platelets in arterial vessels -> substantial mortality & morbidity

  Approx. 30% mortality in West due to arterial thrombosis
• What is the role of platelets?

  Adhesion - stick to damaged tissue

  Shape change & spreading - patch up damaged tissue

  Release stored mediators from granules

  Synthesise mediators (e.g. TxA1 from arachidonic acid)

  Aggregation - stick to each other

  Promote coagulation -> thrombin & fibrin generation
• What is released from dense granules in platelets?

  ADP, ATP, 5-HT etc
• What is released from alpha granules in platelets?

  Fibrinogen, alpha(IIb)beta(3), etc
• How can platelet agrregation be measured?

  Optical aggregometry

  Quantify the optical density of a suspension of activated platelets
• What is integrin a(IIb)b(3)?

  Fibrinogen receptor

  GPIIb/IIIa

  ^ same names
• Where is integrin aIIbb3 found?

  Only expressed on platelets & within alpha granules

  Has high & low affinity states ('inside-out')
• What affinity of aIIbB3 do resting/activated platelets have?

  Resting platelets - low affinity aIIbB3

  Activated platelets - high affinity aIIbB3
• How does aggregation occur?

  Activation of platelets -> change in affinity of aIIbB3 (from low to high) -> fibrinogen can bind to aIIbB3 -> fibrinogen crosslinks activated platelets (binds to another aIIbB3 on another platelet) -> more platelets recruited -> large aggrgate (or thrombus)
• What can activate platelets?

  Collagen - in ECM

  Thrombin - coagulation cascade

  ADP - released from dense granules

  Thromboxane A2

  Platelet activating factor (PAF)

  Adrenaline

  Serotonin (5-HT) - released from dense granules
• What is platelet response to injnury?

  Vessel damage -> loss of endothelial layer -> exposes underlying collagen -> platelets adhere to exposed collagen & become activated -> change in shape, release ADP from granules & synthesise TxA2 -> when more platelets arrive to site, they also become activated -> activated platelets convert integrin aIIbB2 from high to low affinity -> binds to fibrinogen -> aggregration -> formation of primary haemostatic plug (or thrombus)
• Why is aspirin anti-thrombotic?

  Inhibits COX-1 -> blocks synthesis of TxA2 (pro-aggregatory) & PGI2 (anti-aggregatory)

  Less TxA2 -> less aggreation
• Give 3 activatory platelet receptors.

  P2Y12

  TP

  GpVI
• Give 2 inhibitory platelet receptors.

  A2A

  IP