Principles of

antiplatelet therapy
Dr Htet Htet
HtetHtet@imu.edu.my
Lesson outcomes
At the end of the lecture the student should be able to

• discuss the principles of antithrombotic and Thrombolytic Drug Therapy

• describe the clinical pharmacology of drugs used in prevention and treatment

of thromboembolic disorders.
Platelet aggregation Coagulation cascade
& adhesion

https://www.youtube.com/watch?v=0pnpoEy0eYE https://www.youtube.com/watch?v=cy3a__OOa2M
Haemostasis is homeostasis
What is haemostasis?

Haemostasis is the arrest of blood loss from damaged blood vessels a

nd is essential to life.

Process of haemostasis

vasoconstriction, followed by:

• adhesion and activation of platelets (formation of haemostatic plug)
• reinforced by fibrin (end product of coagulation cascade)
Thrombosis is pathological
What is thrombosis?

Thrombosis is the pathological formation of a ‘haemostatic’ plug within the

vasculature in the absence of bleeding (‘haemostasis in the wrong place’).
Complication
Embolism (thromboembolism)

• Thrombus can break away from its attachment and float through the circulation, f

orming an embolus & the process is “embolism”

• Venous emboli usually lodge in a pulmonary artery (‘pulmonary embolism’),

• Arterial thrombus that embolises from the left heart or a carotid artery usually lo

dges in an artery in the brain or other organs, causing death, stroke or other dis

aster.
Different pharmacotherapies for haemostasis
mechanism
Drug therapy to promote haemostasis (antifibrinolytic and haemostatic drugs)

when this essential process is defective.

Drug therapy to treat or prevent thrombosis or thromboembolism (three distinct ways)

blood coagulation (fibrin formation) Anticoagulant drugs

platelet function Anti-platelet drugs

fibrin removal (fibrinolysis). Fibrinolytic drugs/thrombolytic drugs

Anti-platelet drugs
critical role in thromboembolic disease
1. Aspirin
Mechanism of action
inhibits platelet TXA 2 synthesis, by irreversible inhibition of cyclo-oxygenase enzyme.

Route of administration  oral (high presystemic elimination)

Dosage
acute indications (thrombotic stroke) a single dose of approximately 300 mg in order
to achieve rapid substantial (>95%) inhibition of platelet thromboxane synthesis, followed
by regular daily doses of 75 mg.
1. Aspirin
Adverse effects
mainly on the gastrointestinal tract (dose-related) so a low dose (75-80 mg once
daily) is usually recommended for thromboprophylaxis.

Indication
reserved for people at high cardiovascular risk (e.g. previous myocardial infarction),
cardiovascular benefit outweighs the risk of gastrointestinal bleeding.
2. Dipyridamole
Mechanism of action
• inhibiting adenosine uptake and cGMP phosphodiesterase activity.

Pharmacological action
• a vasodilator that also inhibits platelet function
• Dipyridamole by itself has little or no beneficial effect.

Adverse effects
• dizziness, headache and gastrointestinal disturbances;
• unlike aspirin - risk of bleeding – does not increase.
2. Dipyridamole
Indication and status of drug

• modified-release form of dipyridamole reduce the risk of stroke and death in patients
with transient ischaemic attacks by around 15% – similar to aspirin.

• beneficial effects of aspirin and dipyridamole were additive. (primarily used in combin
ation with aspirin to prevent cerebrovascular ischemia.)

• It may also be used in combination with warfarin for primary prophylaxis of

thromboemboli in patients with prosthetic heart valves.

3. Adenosine (P2Y12 ) Receptor Antagonists
Ticlopidine (first introduced, but causes neutropenia and thrombocytopenia.)

Clopidogrel, prasugrel, ticagrelor (currently)

Mechanism of action

inhibit ADP-induced platelet aggregation by irreversible inhibition of P2Y12

receptors to which they link via a disulfide bond.

3. Adenosine (P2Y 12 ) Receptor Antagonists
Important pharmacokinetics Pharmacogenetics
well absorbed orally,
prodrug & is converted into active metabolite by CYP enzymes in the liver
including CYP2C19.
CYP2C19 (poor metabolisers) are at increased risk of therapeutic failure.

Drug interaction
omeprazole (metabolised by CYP2C19)
currently recommends against use with proton pump inhibitors for this reason
3. Adenosine (P2Y 12 ) Receptor Antagonists
Adverse effects

1. risk of haemorrhage

2. dyspepsia, rash, diarrhea (clopidrogrel)

3. blood dyscrasia (more with ticlopidine and rare with clopidrogrel)

4. rash, hypersensitivity (rarely) with Prasugrel

3. Adenosine (P2Y12 ) Receptor Antagonists
Therapeutic uses
1. Clopidogrel (as a single agent)
slightly more effective than aspirin- in reducing outcome of ischaemic stroke,
myocardial infarction.
used instead of aspirin in patients with symptomatic atheromatous disease, (reserved
for patients who are intolerant of aspirin.)

2. Clopidogrel + aspirin- reduction in mortality - acute coronary syndromes (acute myocardial

infarction)

3. Prasugrel - more effective than clopidogrel in acute coronary syndromes,(but causes serious
bleeding.)
4. Glycoprotein IIb/IIIa Receptor Antagonists
Abciximab
human monoclonal antibody Fab fragment directed against the GPIIb/IIIa receptor.
Immunogenicity limits its use to a single administration.
Tirofiban, Eptifibatide
IV infusion due to short half life

Mechanism of action
inhibit platelet activation by
inhibiting ligand binding to the GP IIb/IIIa receptor
4. Glycoprotein IIb/IIIa Receptor Antagonists
Therapeutic use

1. high-risk patients undergoing coronary angioplasty, as an adjunct to heparin and

aspirin. It reduces the risk of restenosis at the expense of an increased risk of

bleeding.
4. Glycoprotein IIb/IIIa Receptor Antagonists

2. Tirofiban, eptifibatide: Given intravenous infusion as an adjunct to aspirin an

d a heparin preparation, they reduce early events in acute coronary syndrome
.
5. Epoprostenol (PGI 2 )
Mechanism of action
• agonist at prostanoid receptors.

Pharmacological action
• causes vasodilatation as well as inhibiting platelet aggregation.

Pharmacokinetics & route of administration

• unstable under physiological conditions and has a half-life of around 3 min, so it is

administered as an intravenous infusion.
5. Epoprostenol (PGI 2 )
Indication & use

• added to blood entering the dialysis circuit in order to prevent thrombosis during haemodialysis,
especially in patients in whom heparin is contraindicated.

• used in severe pulmonary hypertension

• circulatory shock associated with meningococcal septicaemia.

Adverse effects

• related to its vasodilator action include flushing, headache and hypotension.

Therapeutic uses of antiplatelets in general
Arterial thrombosis
1. Prevention of myocardial infarction in patients at high risk
2. Acute myocardial infarction

3. Unstable coronary syndromes

4. Following coronary artery bypass grafting

5. Following coronary artery angioplasty and/or stenting

6. Transient cerebral ischaemic attack (‘ministrokes’) or thrombotic stroke , to prevent recurrence

7. Atrial fibrillation , if oral anticoagulation is contraindicated; or, by specialists, in high-risk situations in comb
ination with anticoagulant.

8. Specialised clinical applications (e.g. in haemodialysis or haemofiltration , or in pulmonary hypertension)

(epoprostenol)
Fibrinolytic system

Drugs affect this system by increasing or

inhibiting fibrinolysis

(fibrinolytic and antifibrinolytic drugs)

fibrinolytic cascade is initiated concomitantly

with the coagulation cascade,

resulting the formation within the coagulum

Interactions with coagulation and
of plasmin, which digests fibrin.
platelet pathways and sites of action
of drugs that modify these systems
Fibrinolytic drugs
Indications
to reopen the occluded arteries in patients with acute myocardial infarction or stroke,

less commonly in patients with life-threatening venous thrombosis or pulmonary

embolism.

Classification

1. Streptokinase
2. Urokinase
3. Recombinant tPA (tissue plasminogen activators)
Alteplase, reteplase, Duteplase, tenecteplase
1. Streptokinase
(plasminiogen activating protein extracted from cultures of streptococci)
Mechanism of action

• Streptokinase is a protein (but not an enzyme in itself) synthesized by streptococci that

combines with the proactivator plasminogen. This enzymatic complex catalyzes the

conversion of inactive plasminogen to active plasmin.

Route of administration: intravenous infusion

Therapeutic use & status

• reduces mortality in acute myocardial infarction, and beneficial effect is additive with aspirin.

• Its action is blocked by antibodies, which appear 4 days or more after the initial dose: its use
should not be repeated after this time has elapsed.
2. Urokinase
Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin.
3. tissue plasminogen activators (t-PA)
Mechanism of action
• Plasminogen can also be activated endogenously by tissue plasminogen activators (t-PAs).
• recombinant tPA - more active on fibrin-bound plasminogen than on plasma plasminogen,
‘clot selective’.
• These activators preferentially activate plasminogen that is bound to fibrin, which confines
fibrinolysis to the formed thrombus and avoids systemic activation.
3. tissue plasminogen activators (t-PAs)
Status of t-PAs

• Recombinant human t-PA – Alteplase, reteplase, Duteplase, tenecteplase

• Recombinant tPA is not antigenic

• Reteplase & tenecteplase

• effective as alteplase

• simpler dosing schemes (longer half-lives.)

3. tissue plasminogen activators (t-PAs)
Untoward effects
1. bleeding, including gastrointestinal haemorrhage and haemorrhagic stroke. (If serious, this c
an be treated with tranexamic acid, fresh plasma or coagulation factors.) (major untoward
effect)
2. allergic reactions and low-grade fever (Streptokinase) - generating kinins, and can cause hy
potension by this mechanism.

Contraindications
1. active internal bleeding,
2. haemorrhagic cerebrovascular disease,
3. bleeding diatheses, pregnancy, uncontrolled hypertension, invasive procedures in which
haemostasis is important, and recent trauma – including vigorous cardiopulmonary
resuscitation
3. tissue plasminogen activators (t-PAs)
Therapeutic indications

1. pulmonary embolism

2. severe deep venous thrombosis (e.g. superior vena caval syndrome, ascending
thrombophlebitis of the iliofemoral vein with severe lower extremity edema)

3. intra-arterially, especially for peripheral vascular disease.

4. management of acute myocardial infarction requires careful patient selection,

5. Recombinant t-PA has also been approved for use in acute ischemic stroke
within 3 hours of symptom onset.
Arterial thrombosis (Principles of therapy)
Antithrombotic Management of Arterial Thrombosis (role of antiplatelets)
• Activation of platelets is considered an essential process for arterial thrombosis

• aspirin and clopidogrel or ticlopidine (TIAs and strokes or unstable angina and acute
myocardial infarction.)

• prasugrel and ticagrelor are alternatives to clopidogrel for patients with acute corona
ry syndromes managed with percutaneous coronary interventions.

• In stable angina and infarction, these drugs are often used in conjunction with β bloc
kers, calcium channel blockers, and fibrinolytic drugs.
Venous thrombosis (Principles of therapy)
Antithrombotic Management of venous thrombosis. (role of anticoagulants)

• Prevention/ Treatment of established disease

• Heparin and warfarin - prevention and treatment of venous thrombosis.

toxicity – vitamin K (warfarin inhi
bits synthesis of vit K dependent
Treatment of warfarin overdose/

• Subcutaneous low-dose unfractionated heparin, LMW heparin, or fondaparinux

clotting factors (II, VII, IX, X)

• Warfarin (monitoring of prothrombin time.)

Treatment of heparin overdose/toxicity –
Caution protamine sulphate
• Warfarin readily crosses the placenta.
• cause hemorrhage at any time during pregnancy as well as developmental defects in the fetus
when administered during the first trimester.
• venous thromboembolic disease in pregnant women – heparin SC injection (best treatment)
Antiplatelet agents (Summary)
1. Aspirin - COX inhibition
2. Dipyridamole - PDE inhibitor
3. Ticlopidine, Clopidrogrel, prasugrel - P2Y 12 receptor inhibitor
4. Abciximab, Tirofiban, Eptifibatide – glycoprotein IIb IIIa inhibitor

5. Epoprostenol - PGI 2

Thrombolytic agents/ fibrinolytic agents (Summary)

1. Streptokinase, urokinase - conversion of inactive plasminogen to active plasmin.

2. Alteplase, reteplase, tenecteplase - preferentially activate plasminogen that is bound to fibrin

Anticoagulant agents (summary)
1. Wafarin – inhibits vitamin K dependant clotting factor synthesis (II, VII, IX, X)

2. Heparin – indirect thrombin inhibitor, binds with antithrombin III and enhance its inactivation of factor Xa.
3. Direct factor Xa inhibitors (oral) - rivaroxaban, apixaban, and edoxaban represent a new class of oral an
ticoagulant drugs that require no monitoring. inhibit factor Xa, in the final common pathway of clotting.

4. Direct Thrombin Inhibitors - directly binding to the active site of thrombin, thereby inhibiting thrombin’s
downstream effects.

i. Parenteral Direct Thrombin Inhibitors –

i. (leech extract) Hirudin

ii. Bivalirudin,
iii. Argatroban

ii. Oral Direct Thrombin Inhibitors (Dabigatran)

Reference
1. Rang, HP. Ritter, JM. Flower, RJ. Henderson, G.. (2016). Haemostasis and thrombosis . In: Rang

and Dale Pharmacology . 8th ed. London: Elsevier. 293-307.

2. Zehnder JL. Drugs Used in Disorders of Coagulation. In: Katzung BG, Trevor AJ.eds. Basic & Clin

ical Pharmacology, 13e. New York, NY: McGraw-Hill; 2015. http://accessmedicine.mhmedical.com

/content.aspx?bookid=1193&Sectionid=69108955. Accessed November 30, 2016.

3. https://www.thrombosisadviser.com/images-library-about-venous-arterial-thrombosis/ Accessed N

ovember 30, 2016.