COAGULATION AND ASPIRIN

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COAGULATION AND ASPIRIN

• By Nina Kassett nina.kassett_at_utoronto.ca
• Olivia Peicu olivia.peicu_at_utoronto.ca
• My-Linh Nguyen ml.nguyen_at_utoronto.ca
• Joshua Lieblein joshua.lieblein_at_utoront
  o.ca
• Sign Up Date January 8th, 2008

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BLOOD COMPOSITION

• Total volume of blood in a
• normal healthy adult is about
• 5.5 litres (2)
• Hematocrit contribution
• of erythrocytes
• Platelets (thrombocytes)
• are involved in hemostasis ?cessation of
  bleeding
• One mechanism of hemostasis is the formation of a
  blood clot. A blood clot is a platelet plug.

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THE PLATELET PLUG

• After initial blood vessel damage, aggregated
  platelets will release Thromboxane A2 (TXA2)
  which causes the recruitment of more platelets.
• This creates the Platelet Plug(2)

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COAGULATION CASCADE

• Extrinsic Pathway Initiated due
• to tissue factor (TF) that leaks into
• blood vessels from outside
• (i.e. external to) the blood vessel (4)
• i.e. Laceration
• Intrinsic Pathway Activators are
• either in direct contact with the
• blood or are contained within
• (i.e. intrinsic to) the blood.
• Outside damage is not needed.(4)
• i.e. Roughened or damaged
• endothelial cells

Modified from www.strokecenter.org/.../gage/anti_
throm_03.htm

• The platelet plug initially blocks blood leakage
  at the site of damage. This in combination with
  the coagulation cascade leads to hemostasis.

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COAGULATION CASCADE
EXTRINSIC AND INTRINSIC PATHWAYS
Coumadin
Razaxaban
Clotting Factors I - XIII
Prothrombin Thrombin
Fibrinogen Fibrin
http//www.britannica.com/eb/art-94920/Red-blood-c
ells-trapped-in-a-mesh-of-fibrin-threads
Fig 1. Cascade of activation steps leading to
blood clotting(6) Extrinsic and intrinsic
pathways are two routes which form blood clots.
The extrinsic pathway is initiated by factors
which are released from injured tissues. On the
other hand, intrinsic pathways are initiated when
the blood comes into contact with abnormal
surfaces caused by injury. Thrombin converts
fibrinogen, a zymogen, into active fibrin.
Fibrin then aggregates into fibrous arrays which
are stabilized by covalent crosslinks.
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ASPIRIN

• Aspirin acetylsalicylic acid
• NSAID Non-steroidal Anti-inflammatory Drug
• Has a good Hydrophillic-Lipophillic Balance,
  therefore it is easily absorbed by passive
  diffusion across membranes(3)

• Uses(3)
• Anti-inflammatory
• Anti-pyretic
• Analgesic
• Platelet forming inhibitor
• Mechanism of Action inhibits
• Cyclooxygenase enzyme (COX)
• via acetylation

http//www.pharmaceutical-technology.com/projects/
kondirolli/kondirolli5.html
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CYCLOOXYGENASE (COX)

• There are two types of
• COX enzymes, COX1 and COX2(5)
• COX1(2)
• Responsible for producing
• Prostaglandins (PG) that
• maintain homeostasis
• Regulates the secretion of gastric
• mucins via PGE2
• Produces precursors of
• Thromboxane A2 (TXA2) which
• recruits additional platelets to the
• platelet plug
• Produces Prostacyclin (PGI2)
• which inhibits platelet aggregation
• Always active
• COX2(2)
• Responsible for producing Prostaglandins
  associated with pain and inflammation
• Becomes active upon tissue damage or infection

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MECHANISM OF ACTION OF ASPIRIN

• Aspirin non-selectively inhibits the COX enzymes
  via acetylation
• (discovered by John Vane, Nobel prize
• winner in 1982)(7)

• Inhibition of COX2(2)
• Stops production of PG responsible
• for pain and inflammation
• Therefore Aspirin acts as an analgesic and
  anti-inflammatory
• Inhibition of COX1(2)
• Stops production of PGE2 responsible for
  protection of stomach lining
• Therefore Aspirin is known to cause stomach
  ulceration
• At low doses (i.e. 81mg) Aspirin inhibits TXA2.
  The inhibition of TXA2 results in a decrease in
  platelet plug formation which in turn decreases
  coagulation
• At high doses, Aspirin inhibits PGI2. The
  inhibition of PGI2 results in a promotion of
  platelet aggregation(9)

http//nobelprize.org/nobel_prizes/medicine/laurea
tes/1982/vane-autobio.html
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USES(3)

• Low dose acetylsalicylic acid (ASA),
• such as 81mg/day, can be used as a
• treatment for those with heart
• disease or for high-risk individuals
• over the age of 30
• Shown to reduce stroke, myocardial
• infarction, and vascular deaths(1)
• Reduces the risk for vascular mortality in
  patients with suspected acute myocardial
  infarctions
• Reduce the risk of transient ischemic attacks
• Prophylaxis for venous thromboembolism
• Relief of inflammation from arthritis, bursitis,
  sprains and strains etc...
• Relief of fever

www.brighamandwomens.org/.../PressRelease.aspx
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VIOXX

• Vioxx selectively inhibits COX2 enzyme(8)
• This is advantageous because it eliminates the
  side effects of stomach ulceration associated
  with COX1 inhibition.
• However, for reasons unknown, it was associated
  with higher risks of heart attacks and strokes
  with
• long-term and
• high-dosage
• usage

http//www.vioxx-lawsuit.ca/
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REFERENCES

• Hopkin. Diabetes Care. Patient Self-Care.
  Ottawa Canadian Pharmacist Association. 2002.
  pg. 320
• Stanfield Germann. Principles of Human
  Physiology, 3rd Edition. Toronto Pearson.
  2008. pg. 437
• Aspirin. CPS. 2008.
• Tortora Grabowski. Principles of Anatomy
  Physiology. New York John Wiley Sons Inc.
  2003.
• Nelson Cox. Principles of Biochemistry, 4th
  Edition. New York W H Freeman and Company.
  2005.
• Wong, Crain, et al. Razaxaban, a direct factor
  Xa inhibitor, in combination with aspirin and/or
  clopidogrel improves low-dose antithrombotic
  activity without enhancing bleeding liability in
  rabbits. J Thromb Thrombolysis. 24 43-51.
  2007.
• http//nobelprize.org/nobel_prizes/medicine/laurea
  tes/1982/press.html
• Cavusgil. Merck and Vioxx An Examination of an
  Ethical Decision-Making Model. Journal of
  Business Ethics. 76 451-461. 2007
• Gurbel, Becker, et al Platelet function
  monitoring in Patients with Coronary Artery
  Disease. Journal of the American College of
  Cardiology. Vol 50, No 19, 2007.

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Sumary Slide

• two types of COX enzymes, COX1 and COX2(5)
• COX1(2)
• Responsible for producing
• Prostaglandins (PG) that
• maintain homeostasis
• Regulates the secretion of gastric
• mucins via PGE2
• Produces precursors of
• Thromboxane A2 (TXA2) which
• recruits additional platelets to the
• platelet plug
• Produces Prostacyclin (PGI2)
• which inhibits platelet aggregation
• Always active
• COX2(2)
• Responsible for producing Prostaglandins
  associated with pain and inflammation
• Becomes active upon tissue damage or infection
• Aspirin non-selectively inhibits the COX enzymes
  via acetylation