Anti Platelet Medication

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Anti Platelet Medication
By Mehdi Khosravi, M.D.
Internal Medicine Residency Michigan State
University B-301 Clinical Center East Lansing, MI
48824
Phone [phone] Fax [phone] Email
khosrav1_at_msu.edu
To contact us
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Anti Platelet Medication
Platelets are anucleated blood cells that
participate in hemostasis by providing a
negatively charged phospholipids surface for
Factor X and Prothrombin activation reactions.
They also release substances such as Serotonin
that mediate blood vessel contraction and
Thromboxane A-2 that cause other platelets to
aggregate. Platelet functions are classically
described as Adhesion, Aggregation, Activation
and Consolidation These functions are depicted
in the figure bellow. Modulation of these
functions is used to treat arterial thrombotic
disease . In following sections different
medications and their therapeutic roles will be
further elucidated.
Anti Platelet Medication Aspirin and NSAIDs
Dipyridamole Ticlopidine and Clopidogrel
Glycoprotein IIb/IIIa Antagonists
Thromboxane-Synthase Inhibitors Other
Anti-Platelet Medications Appendix 1 Appendix
2 Appendix 3
Slide Adapted from Signal Transducing
PathwaysJacek Hawiger, MD, PhD Platelet in
Thrombosis and Rethrombosis, Molecular
Cardiovascular Medicine, Ch. 11, 1995.
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Aspirin and NSAIDs
Aspirin was synthesized in 1897. The drug was
introduced to medical community in 1899 by Bayer
company. The anti platelet action is caused by
irreversible inhibition of Cycloxygenase-1
(COX-1) enzyme by acetylation of hydroxyl group
of a serine residue at enzymes active site.
This will in turn block production of
Thromboxane A2 (as shown in figure bellow). The
effect can only be overcome by production of new
COX-1 enzyme. Since platelets lack this ability,
the effect of Aspirin is irreversible in them and
last for their lifetime. The effect is increase
in bleeding time. The anti-platelet dose starts
at 30 to 75 mg once a day. The only disadvantage
of this low dose is that it takes several days to
achieve the maximum effect. This can be overcome
by a loading dose of 120 mg. This has the same
effect of 325 mg daily dose. Aspirin is mostly
absorbed in small intestine. Its bioavailability
is between 40 to 50 percent. Aspirins effective
half life including its active metabolite,
Salicylate, is 2 to 12 hours and is dose
dependant. It has a first order elimination
through kidneys. Aspirin is used in management of
Stable Angina (75 mg), Unstable Angina (75 mg),
Prevention Coronary Artery Graft Occlusion and
Acute Myocardial Infarction (160 mg). It is also
used in management of TIA (50 mg) and Ischemic
Stroke (160 mg) with or without other agents such
as Dipyridamole. Other NSAIDs inhibit the COX
enzyme in an reversible way. Of these
Sulfinpyrazone, Indobufen and Triflusal have been
tested in randomized trials. None of these
medications are approved by FDA for use in USA.
The Initial Diagram Adapted, Modified and
Animated by M. Khosravi, MD. From Signal
Transducing PathwaysJacek Hawiger, MD, PhD
Platelet in Thrombosis and Rethrombosis,
Molecular Cardiovascular Medicine, Ch. 11 157,
1995.
Anti Platelet Medication Aspirin and NSAIDs
Dipyridamole Ticlopidine and Clopidogrel
Glycoprotein IIb/IIIa Antagonists
Thromboxane-Synthase Inhibitors Other
Anti-Platelet Medications Appendix 1 Appendix
2 Appendix 3
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Dipyridamole
Dipyridamole (Persantine) is a
Pyrimidopyrimidine derivative. It has both
vasodilator and anti-platelet activity. There is
controversy in its mechanism of action. Two
theories have been suggested Blockade of
Adenosine uptake and Inhibition of Cyclic
Nucleotide Phosphodiesterase both resulting in
increase in cAMP. Dipyridamole has variable
and low oral bioavailability. It is mainly
excreted from liver and goes through
enterohepatic recirculation. Its half life is
approximately 10 hours. A new formulation with
better bioavailability mixed with Aspirin with
trade name of Aggronox has recently been shown
effective for management of stroke.
Dipyridamole is also used for its vasodilator
action in Cardiolyte stress test.
The Initial Diagram Adapted, Modified and
Animated by M. Khosravi, MD. From Signal
Transducing PathwaysJacek Hawiger, MD, PhD
Platelet in Thrombosis and Rethrombosis,
Molecular Cardiovascular Medicine, Ch. 11 157,
1995.
Anti Platelet Medication Aspirin and NSAIDs
Dipyridamole Ticlopidine and Clopidogrel
Glycoprotein IIb/IIIa Antagonists
Thromboxane-Synthase Inhibitors Other
Anti-Platelet Medications Appendix 1 Appendix
2 Appendix 3
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Ticlopidine and Clopidogrel
Ticlopidine (Ticlid) and Clopidogrel (Plavix)
are structurally related thienopyridines. They
both inhibit ADP-induced platelet aggregation.
Both of these medications are inactive in vitro
and they need hepatic transformation to active
metabolite(s). They irreversibly change ADP
receptor. Ticlopidine has 90 percent oral
bioavailability. It is extensively metabolized in
liver. 98 percent of it is protein bound. On the
other hand, Clopidogrel cannot be detected in
free form in plasma. The main metabolite of
Clopidogrel is SR-26334 that has half life of 8
hours. The anti-platelet activity of Ticlopidine
develops slower than Clopidogrel (2 weeks versus
2 hours). Ticlopidine has the same efficacy
as Aspirin yet because of its side effects namely
hypercholesterolemia and neutropenia and its
expense, it is not preferred as a substitute for
Aspirin. There is recent interest of using it
with Aspirin as adjuvant therapy for patients
going through PTCA. Clopidogrel has the same
efficacy as Aspirin in management of acute
myocardial infarction and stroke. It also has
safety comparable to medium dose Aspirin.
The Initial Diagram Adapted, Modified and
Animated by M. Khosravi, MD. From Signal
Transducing PathwaysJacek Hawiger, MD, PhD
Platelet in Thrombosis and Rethrombosis,
Molecular Cardiovascular Medicine, Ch. 11 157,
1995.
Anti Platelet Medication Aspirin and NSAIDs
Dipyridamole Ticlopidine and Clopidogrel
Glycoprotein IIb/IIIa Antagonists
Thromboxane-Synthase Inhibitors Other
Anti-Platelet Medications Appendix 1 Appendix
2 Appendix 3
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Glycoprotein IIb/IIIa Antagonists
After it was found that expression of
glycoprotein IIb/IIIa is the common pathway for
platelet aggregation, the quest for developing
inhibitors of this glycoprotein was started.
These inhibitors include Monoclonal antibodies
against the receptor (Abciximab or ReoPro),
Natural RGD-containing peptides (found in viper
venom Trigramin, Bitistatin, Echistatin,
Kistrin, Barbourin and Applagin), Synthetic RGD
or KGD-containing peptides (Integrilin and
MK-852) and Peptidomimetic or non-peptide RGD
mimetics (Lamifiban, Tirofiban, Fradafiban,
Orbofiban and Xemilofiban). Mechanism of action
of these agents is depicted in figure
bellow. It has been shown that platelet
aggregation almost completely halts with 80
percent inhibition of the receptor although
bleeding time is only mildly affected. At 90
percent blockade the bleeding time will be
extremely extended. Abciximab is currently
approved by FDA for patients undergoing PTCA and
artherectomy. The response to it is dose related
and the effect gradually abolishes in 12 hours.
From the natural RGD-containing peptides,
Barbourin is highly specific for GPIIb/IIIa.
Their problem is that they are highly immunogenic
and cause thrombocytopenia. From KGD-containing
synthetic inhibitors cyclic heptapeptide
Ebtifibatide (Integrilin) are also currently used
in management of PTCA. The synthetic non
peptide RGD mimetics are also going through phase
II and III studies. They are also available in
oral form yet inability to monitor their effects
will affect their out patient use.
Anti Platelet Medication Aspirin and NSAIDs
Dipyridamole Ticlopidine and Clopidogrel
Glycoprotein IIb/IIIa Antagonists
Thromboxane-Synthase Inhibitors Other
Anti-Platelet Medications Appendix 1 Appendix
2 Appendix 3
The Initial Diagram Adapted From Anti-Platelet
DrugsMarc Verstraete, MD, PhD Cardiovascular
Thrombosis, Ch. 8 133, 1998.
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Thromboxane-Synthase Inhibitors
Thromboxane-Synthase Inhibitors prevent further
metabolism of Prostaglandin H-2 (PGH-2).They
transfer the PGH-2 that accumulates in platelets
to endothelial PGI-2 Synthase at the site of
platelet-vessel wall interaction. The
clinical studies have been disappointing,
however, and most pharmaceutical companies have
stopped clinical development of these
compounds. Thromboxane Receptor Antagonists
GR-32191, Ifetroban, Picotamide and Sulotroban
have also had disappointing results in clinical
trials.
The Initial Diagram Adapted, Modified and
Animated by M. Khosravi, MD. From Signal
Transducing PathwaysJacek Hawiger, MD, PhD
Platelet in Thrombosis and Rethrombosis,
Molecular Cardiovascular Medicine, Ch. 11 157,
1995.
Anti Platelet Medication Aspirin and NSAIDs
Dipyridamole Ticlopidine and Clopidogrel
Glycoprotein IIb/IIIa Antagonists
Thromboxane-Synthase Inhibitors Other
Anti-Platelet Medications Appendix 1 Appendix
2 Appendix 3
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Other Anti-Platelet Medications

• Omega-3 Fatty Acids
• Omega-3 Fatty Acids are polyunsaturated fats
  present in non-meat dietary compounds, mainly in
  fish. They incorporate into the platelet membrane
  and cause a reduction in platelet aggregation by
  reducing Arachidonic acid metabolism and the
  production of Thromboxane A-2.
• Cilostazol
• Cilostazol (Pletal) inhibits intracellular
  Phosphodiesterase III activity that increases
  cAMP. It inhibits cellular interaction among
  platelets, leukocytes, and vascular endothelial
  cells mediated by P-Selectin. It can cause
  bronchodilation and suppress mitogenesis.
• Serotonin Antagonists
• Ketanserin and Sarpogrelate are a Serotonin
  Antagonist. They decrease Serotonin induced
  platelet aggregation. They are mainly used for
  other indications such as migraine and anxiety.
• Dextran
• Dextran (Zinecard) acts in two ways It may be
  involved in some alteration of platelet membrane
  function and it may interfere with the Factor
  VIII-Von Willebrand Factor Complex.
• Trapidil (Triazolopyrimidine)
• Trapidil (Triazolopyrimidine) is a
  Platelet-Derived Growth Factor Antagonist.
  Triflusal (2-Acetyloxy-4-Trifluoromethyl Benzoic
  Acid) is an orally active anti-platelet agent.

• Trapidil (Triazolopyrimidine)
• Trapidil (Triazolopyrimidine) is a
  Platelet-Derived Growth Factor Antagonist.
  Triflusal (2-Acetyloxy-4-Trifluoromethyl Benzoic
  Acid) is an orally active anti-platelet agent.
• 2-P-Mercaptophenyl-1, 4-Naphthoquinone or NTP
• 2-P-Mercaptophenyl-1, 4-Naphthoquinone or NTP
  has multiple effects on platelets it decreases
  the percentage of attached platelets at locations
  in various shear stresses, it can inhibit
  platelet aggregation by ADP and Collagen, it also
  markedly inhibits Thromboxane B-2 formation and
  it inhibits platelet Calcium elevation caused by
  ADP and Collagen.
• Vitamin E
• a-Tocopherol in therapeutic doses can inhibit
  platelet aggregation possibly through its
  anti-oxidant and membrane stabilization effects.
• Prostaglandins E-1 and I-2
• Prostaglandins E-1 (Dinoprostone) and I-2
  (Epoprostenol) increase the concentration of
  Cyclic Adenosine Monophosphate (cAMP) in
  platelets. They are potent inhibitors of platelet
  aggregation. They are powerful systemic
  vasodilators and have a short half life that
  decreases their clinical use as platelet
  antagonists.
• Nitric Oxide (NO) Donors
• Guanylyl-Cyclase Activators (S-nitrosoglutathione
  ) are Nitric Oxide (NO) Donors that increase
  Cyclic GMP. They cause severe hemodynamic changes.

Anti Platelet Medication Aspirin and NSAIDs
Dipyridamole Ticlopidine and Clopidogrel
Glycoprotein IIb/IIIa Antagonists
Thromboxane-Synthase Inhibitors Other
Anti-Platelet Medications Appendix 1 Appendix
2 Appendix 3
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Appendix 1
Decrease in Platelet Function
Platelet functions are initiated by signals to
receptors on platelet surface membranes. Decrease
in one or more of the platelet functions leads
to bleeding diatheses (disorders). This is
Illustrated in the Next Diagram by Rao, et al.
Anti Platelet Medication Aspirin and NSAIDs
Dipyridamole Ticlopidine and Clopidogrel
Glycoprotein IIb/IIIa Antagonists
Thromboxane-Synthase Inhibitors Other
Anti-Platelet Medications Appendix 1 Appendix
2 Appendix 3
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Appendix 2
Platelet Receptors
Platelet and Endothelial Cell Receptors for
Signal Transducing Pathways
Platelet and endothelial receptors consist of a
family of Integrins. They are Calcium dependant
cell adhesion molecules that have two a and b
subunits. In Platelets and endothelial cells they
mostly have the same b subunit (b3 family or b1
family) Platelets bind to extra-cellular matrix
components exposed after endothelial detachment,
through Integrin and Non-Integrin Receptors. This
is illustrated in the diagrams bellow
Fibrinogen Receptors
Endothelial Cell Receptors
Anti Platelet Medication Aspirin and NSAIDs
Dipyridamole Ticlopidine and Clopidogrel
Glycoprotein IIb/IIIa Antagonists
Thromboxane-Synthase Inhibitors Other
Anti-Platelet Medications Appendix 1 Appendix
2 Appendix 3
Slides Adapted from Signal Transducing
PathwaysJacek Hawiger, MD, PhD Platelet in
Thrombosis and Rethrombosis, Molecular
Cardiovascular Medicine, Ch. 11 157, 1995.
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MSU Internal Medicine Residency
Appendix 3
Platelet Signal Transducing Pathways
G-Protein Pathway

• Platelet functions are induced by signals.
  Thrombin is the most potent activator of
  platelets through its receptor PAR-1. Thromboxane
  A-2 acts through its own receptor. There are also
  a variety of endogenous and external chemical
  agents including ADP, Epinephrine and Platelet
  Activating Factor (PAF).
• Signal transduction in platelets acts through
  three pathways
• G-Proteins
• Phospholipase C
• Phospholipase A-2
• In the following slides the platelet receptors
  and Transducing pathways are separately
  presented.
• Click here to see a movie of how these pathways
  work.
• Physiologic platelet antagonists include
• Prostaglandins (PGI-2, PGE-2 and PGD-2)
• Nitric Oxide
• Phosphates
• Nitric Oxide increases platelet cGMP levels.
  Prostacyclins block the Thromboxane A-2 receptor.
  

Phospholipase C Pathway
Phospholipase A-2 Pathway
Physiologic Platelet Antagonists
Anti Platelet Medication Aspirin and NSAIDs
Dipyridamole Ticlopidine and Clopidogrel
Glycoprotein IIb/IIIa Antagonists
Thromboxane-Synthase Inhibitors Other
Anti-Platelet Medications Appendix 1 Appendix
2 Appendix 3
The Initial Diagram Adapted, Modified and
Animated by M. Khosravi, MD. From Signal
Transducing PathwaysJacek Hawiger, MD, PhD
Platelet in Thrombosis and Rethrombosis,
Molecular Cardiovascular Medicine, Ch. 11 157,
1995.
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G-Protein Pathway (1)  
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G-Protein Pathway (2)  
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G-Protein Pathway (3)  
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G-Protein Pathway (4)  
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G-Protein Pathway (5)  
Click Here to Go Back to Appendix 3
Click Here to Proceed to Phospholipase C Pathway
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Phospholipase C Pathway (1)  
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Phospholipase C Pathway (2)  
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Phospholipase C Pathway (3)  
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Phospholipase C Pathway (4)  
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Phospholipase C Pathway (5)  
Click Here to Go Back to Appendix 3
Click Here to Proceed to Phospholipase A2
Pathway
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Phospholipase A2 Pathway (1)  
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Phospholipase A2 Pathway (2)  
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Phospholipase A2 Pathway (3)  
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Phospholipase A2 Pathway (4)  
Click Here to Go Back to Appendix 3
Click Here to Proceed to Physiologic Platelet
Antagonists
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Physiologic Platelet Antagonists -  Prostaglandins
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Physiologic Platelet Antagonists -  Phosphates
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Physiologic Platelet Antagonists -  Nitric Oxide
Click Here to Go Back to Appendix 3
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Platelet Receptors and Transducing Pathways
Click on the picture to start or stop the movie
Click Here to Go Back to Appendix 3