Question 20

Describe the structure and function of platelets (50% marks). Outline the pharmacology of clopidogrel (50% marks). 

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College Answer

Platelets are small cells in blood, approximately 150,000 – 300,000 / microliter of blood with a half life of approximately 4 days. They have important membrane receptors (for collagen, vWF  and fibrinogen) and intracellular contents (Actin, Myosin, Glycogen, Lysosomes, Dense granules, Alpha granules) and are involved in forming a platelet plug and clotting. Common omissions were to not give a normal platelet count or half life. Diagrams of the clotting cascade were not required. Clopidogrel is an oral, thienopyridine class antiplatelet agent (a prodrug activated in the liver by cytochrome P450 enzymes), used to inhibit blood clots in coronary artery disease, following stent placement, peripheral vascular disease, and cerebrovascular disease. Mechanism of action is: specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, which is important in  aggregation of platelets and cross-linking by the protein fibrin and thus platelet aggregation, which is inhibited when binding blocks activation of the glycoprotein IIb/IIIa pathway. Elimination half-life of about 8 hours; rapidly absorbed after oral administration; undergoes rapid hydrolysis in liver and renal excretion; 95% protein bound. Important interactions/precautions include proton pump inhibitors, phenytoin, warfarin, heparin, danaparoid, enoxaparin and various thrombolytics. Greatest risk is bleeding. The best answers had a structured approach to describing a drug.


  • Structure of platelets
    • Small (0.5-3μm) irregular anucleate cells
    • Contain:
      • Mitochondria, ATP and glycogen
      • Dark granules and α-granules
      • Microtubules and surface-connected canaliculi
  • Function of platelets
    • Adhesion to the denuded surface collagen via VWF, as well as directly
    • Aggregation (platelet to platelet) mediated by fibrin and VWF
    • Activation, which means
      • Degranulation (release of vasoactive and platelet-activating mediators)
      • Shape change (flattening and extension of cellular projections)
      • Phosphatidylserine exposure on the platelet surface, which is essential for clotting factor binding
    • Amplification
      • Intrinsic pathway activation by the available thrombin and other platelet granule content leads to the increase in available clotting factors in the region of the platelet plug
      • The available thrombin activates factor XI and leads to the activation of FXI
      • Activate platelet surfaces act as sites of attachment for FVIIIa and FVa
    • Propagation
      • Platelet-bound Factors FVIIIa  FVa and FX activate thrombin
      • This leads to the formation of a large amount of thrombin (the "thrombin burst")
      • The large amount of thrombin made available allows the generation of a large amount of fibrin from fibrinogen
    • Contraction of platelets occurs in later stages of clot maturation

So... Clopidogrel?

Class Antiplatelet agent
Chemistry Thienopyridine
Routes of administration Oral
Absorption Absorption is poor (50%) and bioavailability is even worse - only 2% of the oral dose is converted to the active metabolite
Solubility pKa 3.5; basically insoluble in water
Distribution VOD=550L/kg; 98% protein-bound
Target receptor P2Y12 class of ADP receptor
Metabolism Complex hepatic metabolism,. where most of the absorbed dose is hydrolysed by carboxylesterase 1 into an inactive carboxylic acid metabolite, and onyl 2% is converted to clop-AM, the pharacologically active form of clopidogrel.
Elimination Of the metabolites, 50% are eliminated in the urine, and 50% in the faeces
Time course of action Clopidogrel has a half-life of 6 hours, and the active metabolite has a half-life on only 30 minutes.
Clinical effect duration: 7-10 days
Mechanism of action By inhibits the binding of ADP to the P2Y12 receptor, clopidogrel prevents platelet activation, and the subsequent ADP- mediated activation of the glycoprotein GPIIb/IIIa complex. Thus, both platelet activation and platelet aggregation are affected. This effect is irreversible
Clinical effects Risk of bleeding (which is serious!), aplastic anemia, thrombocytopenia, and neutropenia
Single best reference for further information TGA PI document


Jurk, Kerstin, and Beate E. Kehrel. "Platelets: physiology and biochemistry." Seminars in thrombosis and hemostasis. Vol. 31. No. 04. Copyright© 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA., 2005.

Linden, Matthew D. "Platelet physiology." Haemostasis. Humana Press, Totowa, NJ, 2013. 13-30.

Gremmel, Thomas, Andrew L. Frelinger III, and Alan D. Michelson. "Platelet physiology." Seminars in thrombosis and hemostasis. Vol. 42. No. 03. Thieme Medical Publishers, 2016.

Kaushansky, Kenneth. "Thrombopoiesis." Seminars in hematology. Vol. 52. No. 1. WB Saunders, 2015.

Schulze, H., and R. A. Shivdasani. "Mechanisms of thrombopoiesis." Journal of thrombosis and haemostasis 3.8 (2005): 1717-1724.

Li, Chunjian, et al. "Reversal of the anti‐platelet effects of aspirin and clopidogrel." Journal of Thrombosis and Haemostasis 10.4 (2012): 521-528.

Plosker, Greg L., and Katherine A. Lyseng-Williamson. "Clopidogrel." Drugs 67.4 (2007): 613-646.

Savi, P., et al. "Clopidogrel: a review of its mechanism of action." Platelets 9.3-4 (1998): 251-255.