Clopidogrel Pharmacology

Master answer

PLATELET

Formation

• produced during hematopoiesis in a sub-process called thromopoiesis, or production of thrombocytes.
• Bone marrow: Common myeloid progenitor cells → promegakaryocytes → megakaryocytes
• Megakaryocytes produce protoplatelets within their cytoplasm → released in cytoplasmic extensions upon cytokine stimulus
  • Protoplatelets break up into hundreds of platelets that circulate throughout the bloodstream
  • The remaining nucleus of the ruptured megakaryocyte is consumed by macrophages.
• Megakaryocyte and platelet production is regulated by thrombopoietin (hormone produced by the liver and kidneys)
• Thrombopoietin stimulates differentiation of myeloid progenitor cells into megakaryocytes and causes the release of platelets.
• Thrombopoietin is regulated by a negative feedback mechanism based on platelet levels
• Each megakaryocyte produces between 5,000 and 10,000 platelets
• Altogether, around 10¹¹ platelets are produced each day in a healthy adult

Fate

• Average lifespan of a platelet is 5 to 10 days
• Old platelets are destroyed by macrophage phagocytosis in the spleen and by Kupffer cells in the liver
• Up to 40% of platelets are stored in the spleen as a reserve, released when needed by sympathetically-induced splenic muscle contractions during severe injury.

Structure

• Small anucleated cells derived from megakaryocytes which originate from haematopoietic stem cell
• Normally 150~300 x 10³ /μl

• Actin and myosin
• Remnants of the ER, SR storing calcium
• Mitochondria
• Enzyme systems → production of prostaglandins
• α granules
  • Thrombin
  • PDGF
  • P-selectin
  • Fibronectin
  • vWF
• Dense granules
  • ADP
  • ATP
  • Ca²⁺
  • Serotonin
  • Histamine

Function

• Haemostasis
  • Formation of platelet plug
    • Interact with collagen exposed at damaged endothelium by GPIa
    • Activated by PAF, Thrombin
      • Morphological change → irradiating pseudopods
      • Degranulation
      • Aggregation
        • Expression of GPIIb/IIIa → binds fibrin and vWF
• Immunomodulation
  • Deployed to sites of inflammation and infection and secrete cytokines and chemokines

Sakurai / JC 2019

Pharmacology of Clopidogrel

Answer by JC, Sakurai