PHA423 7 Antiplatelets CD

PHA 423 – Pharmacology IV
2024/2025 Fall Term

Dr. Cansu Demirbatır
cansu.demirbatir@neu.edu.tr
Office: 2 nd floor opposite the elevator

Antiplatelets –
Lecture 7
Hemostasis
• Thrombosis, the formation of an unwanted
clot within a blood vessel, is the most common
abnormality of hemostasis.
• Hemo means “blood”, stasis means “to stop”.
• Hemostasis is a process to prevent and stop

bleeding, meaning to keep blood within a
damaged blood vessel (the opposite of
hemostasis is hemorrhage).
• It is the first stage of wound healing.
• Thrombotic disorders include acute myocardial

infarction, deep vein thrombosis, pulmonary
embolism, and acute ischemic stroke.
Hemostasis
• Primary Hemostasis: formation of platelet plug at the site of injured blood vessel.
• Secondary hemostasis: multiple coagulation factors working together to form a fibrin mesh
to stabilize the platelet plug.
• Together, these two processes create a blood clot which stops bleeding.
• If the blood clot happens in a coronary artery > it can lead to heart attack.
• If the blood clot travel to the brain > it can lead to stroke.
Thrombus vs Embolus
• A clot that adheres to a vessel wall is called
a “thrombus,” whereas an intravascular clot
that floats in the blood is termed an
“embolus.”
• Arterial thrombosis usually consists of a
platelet-rich clot.
Resting platelets
• Platelets act as vascular sentries, monitoring the integrity of
the endothelium.
• In the absence of injury, resting platelets circulate freely,

because the balance of chemical signals indicates that the
vascular system is not damaged.
• Chemical mediators, such as prostacyclin and nitric oxide, are

synthesized by intact endothelial cells and act as inhibitors of
platelet aggregation.
GP IIb/IIIa receptors
• GP IIb/IIIa receptors, also known as integrin αIIbβ3, are
essential glycoproteins found on the surface of platelets.
• They play a crucial role in blood clotting by allowing platelets

to stick together and form a plug at the site of a wound.
• GP IIb subunit: This subunit has a large extracellular region

that binds to various ligands, including fibrinogen and von
Willebrand factor.
• GP IIIa subunit: This subunit has a smaller extracellular

region and a cytoplasmic tail that interacts with the platelet
cytoskeleton.
GP IIb/IIIa receptors
• Damaged endothelial cells synthesize less prostacyclin,
resulting in a localized reduction in prostacyclin levels.
• The binding of prostacyclin to platelet receptors is
decreased, resulting in lower levels of intracellular cAMP,
which leads to platelet aggregation.
• When a blood vessel is injured, platelets are activated and
change shape. This activation causes a conformational
change in the GP IIb/IIIa receptors, exposing their binding
sites.
• Fibrinogen, a large protein in the blood, binds to these
receptors, linking platelets together and forming a platelet
plug.
Platelet Adhesion
• The platelet membrane also contains receptors that can bind
thrombin, thromboxanes, and exposed collagen.
• When these receptors are occupied, each of these receptor types

triggers a series of reactions leading to the release into the
circulation of intracellular granules by the platelets.
• This ultimately stimulates platelet aggregation.

Platelet Activation
• This causes morphologic changes in platelets and
the release of platelet granules containing
chemical mediators, such as adenosine
diphosphate (ADP), thromboxane A2, serotonin,
platelet-activation factor (PAF), and thrombin.
• These signaling molecules bind to receptors in the

outer membrane of resting platelets circulating
nearby.
• These actions are mediated by several

messenger systems that ultimately result in
elevated levels of calcium and a decreased
concentration of cAMP within the platelet.
Platelet Activation
• Fibrinogen, a soluble plasma GP, simultaneously binds to GP IIb/IIIa receptors on two

separate platelets, resulting in platelet cross-linking and platelet aggregation.
Formation of platelet-fibrin plug
• Local stimulation of the coagulation cascade by tissue
factors released from the injured tissue and by mediators
on the surface of platelets results in the formation of
thrombin (Factor IIa).
• In turn, thrombin, a serine protease, catalyzes the

hydrolysis of fibrinogen to fibrin, which is incorporated into
the plug.
• Subsequent cross-linking of the fibrin strands stabilizes

the clot and forms a hemostatic platelet-fibrin plug.
Fibrinolysis
• During plug formation, the fibrinolytic pathway is locally
activated.
• Plasminogen is enzymatically processed to plasmin

(fibrinolysin) by plasminogen activators in the tissue.
• Plasmin limits the growth of the clot and dissolves the

fibrin network as wounds heal.
• At present, a number of fibrinolytic enzymes are

available for treatment of myocardial infarctions,
pulmonary emboli, and ischemic stroke.
Antiplatelets
1. Cyclooxygenase (COX) Inhibitors
2. Adenosine Diphosphate (ADP)

Receptor Inhibitors
3. Glycoprotein (GP) IIb/IIIa Receptor

Inhibitors
4. Phosphodiesterase (PDE)
Inhibitors
5. Protease-activated receptor-1
(PAR-1) antagonist
Thromboxane A2 Synthesis Pathway
1. Arachidonic Acid Release:
Phospholipase A2 (PLA2) releases
arachidonic acid from membrane
phospholipids.
2. Cyclooxygenase (COX) Conversion:
Arachidonic acid is converted to
prostaglandin H2 (PGH2) by COX
enzymes (COX-1 and COX-2).
3. Thromboxane Synthase: PGH2 is
converted to TXA2 by thromboxane
synthase.
4. TXA2 Actions: TXA2 is a potent platelet
activator and vasoconstrictor. It promotes
platelet aggregation and blood clot
formation.
Aspirin's Mechanism of Action:
• Aspirin irreversibly acetylates COX-1, inhibiting the formation of PGH2 and
subsequent TXA2 synthesis.
• This leads to reduced platelet activation and aggregation, making aspirin an
effective antiplatelet drug.
• Aspirin (acetylsalicylic acid).
Aspirin's Mechanism of Action:

• Acetylates a serine residue in
the active sites for COX-1, which
irreversibly inhibits this enzyme.
2. Adenosine Diphosphate (ADP) Receptor
Inhibitors
P2Y12 Receptor Inhibitors:
• Clopidogrel (Plavix): Prodrug that irreversibly blocks

P2Y12 receptors on platelets, inhibiting ADP-induced
platelet aggregation.
• Prasugrel: More potent prodrug than clopidogrel, also

irreversibly blocks P2Y12 receptors.
• Ticagrelor: Non-prodrug that reversibly blocks P2Y12

receptors, offering faster onset of action compared to
clopidogrel and prasugrel.
3. Glycoprotein (GP) IIb/IIIa Receptor
Inhibitors
Parenteral agents:
• Abciximab: Monoclonal antibody that irreversibly

blocks GPIIb/IIIa receptors, preventing fibrinogen
binding and platelet aggregation.
• Eptifibatide: Peptide that reversibly blocks

GPIIb/IIIa receptors.
• Tirofiban: Non-peptide compound that reversibly

blocks GPIIb/IIIa receptors.
4. Phosphodiesterase (PDE) Inhibitors
• PDE Activity: PDE enzymes degrade cAMP and cGMP, thereby limiting their signaling
effects.
• Platelets express multiple PDE isoforms, including PDE2, PDE3, and PDE5.
• PDE inhibition leads to an increase in intracellular cAMP and cGMP levels, which inhibits
platelet activation and aggregation.
• Dipyridamole: Inhibits PDE III and PDE V, increasing intracellular cyclic adenosine
monophosphate (cAMP) levels, which inhibits platelet activation and aggregation.
• Cilostazol: Inhibits PDE III and phosphodiesterase type 1 (PDE1), leading to increased
cAMP and cyclic guanosine monophosphate (cGMP) levels, respectively, which inhibits
platelet activation and causes vasodilation.
4. Phosphodiesterase (PDE) Inhibitors
5. Protease-activated receptor-1 (PAR-1)
antagonist
• They work by inhibiting the action of thrombin, a potent platelet activator, on the protease-
activated receptor-1 (PAR-1) on the surface of platelets.
• This prevents thrombin-induced platelet activation and aggregation, thus reducing the risk of
blood clot formation.
• Vorapaxar is the only PAR-1 antagonist currently approved for clinical use. However, it is
not widely used due to its increased risk of bleeding.
Antiplatelets
Resources
• Lippincott Pharmacology Book
• Goodman & Gilman’s Pharmacological Basis of Therapeutics
• Katzung & Trevor Pharmacology Book
• Rang and Dale’s Pharmacology Book
Thank you for Listening !

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PHA 423 – Pharmacology IV

2024/2025 Fall Term

Office: 2 nd floor opposite the elevator

• Hemo means “blood”, stasis means “to stop”.

• Hemostasis is a process to prevent and stop

• It is the first stage of wound healing.

• Thrombotic disorders include acute myocardial

• A clot that adheres to a vessel wall is called

a “thrombus,” whereas an intravascular clot

that floats in the blood is termed an

• Arterial thrombosis usually consists of a

• In the absence of injury, resting platelets circulate freely,

• Chemical mediators, such as prostacyclin and nitric oxide, are

• They play a crucial role in blood clotting by allowing platelets

• GP IIb subunit: This subunit has a large extracellular region

• GP IIIa subunit: This subunit has a smaller extracellular

• When these receptors are occupied, each of these receptor types

• This ultimately stimulates platelet aggregation.

• These signaling molecules bind to receptors in the

• These actions are mediated by several

• Fibrinogen, a soluble plasma GP, simultaneously binds to GP IIb/IIIa receptors on two

• In turn, thrombin, a serine protease, catalyzes the

• Subsequent cross-linking of the fibrin strands stabilizes

• Plasminogen is enzymatically processed to plasmin

• Plasmin limits the growth of the clot and dissolves the

• At present, a number of fibrinolytic enzymes are

1. Cyclooxygenase (COX) Inhibitors

2. Adenosine Diphosphate (ADP)

3. Glycoprotein (GP) IIb/IIIa Receptor

Aspirin's Mechanism of Action:

• Clopidogrel (Plavix): Prodrug that irreversibly blocks

• Prasugrel: More potent prodrug than clopidogrel, also

• Ticagrelor: Non-prodrug that reversibly blocks P2Y12

• Abciximab: Monoclonal antibody that irreversibly

• Eptifibatide: Peptide that reversibly blocks

• Tirofiban: Non-peptide compound that reversibly

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