Principles of antiplatelet,

anticoagulant and
fibrinolytic therapies

Module:
Hematology

Prof. Dr. Renu Agarwal

RenuAgarwal@imu.edu.my
Lesson outcomes
1. Discuss the principles of Antithrombotic and Thrombolytic
Drug Therapy
2. Describe the clinical pharmacology of drugs used in
prevention and treatment of thromboembolic disorders
Haemostasis
Vascular injury

Platelet activation Antiplatelets √

adherence

Thrombin and fibrin

generation
Anticoagulants √

Fibrinolysis Thrombolytics √
 Acute Coronary Syndrome
 ACS is a medical emergency
 Main clinical symptom - chest pain because of acute
myocardial ischemia

Because of acute coronary thrombosis

 Coronary
Thrombosis

Fibrin thrombus (Red clot) Platelet thrombus (White clot)

ST segment
depression
Acute Coronary Syndrome

ACS

Myocardial infarction (MI) Unstable Angina

ST elevation Non ST
MI elevation MI
(STEMI) (NSTEMI)

ST segment depression
ANTIPLATELET DRUGS
Platelet aggregation
THROMBUS

INJURY

Platelet Platelet Platelet

ADHESION ACTIVATION AGGREGATION

• Von Willebrand factor • Thromboxane A2 • GP IIb/IIIa

• Collagen • ADP • Fibrinogen

Antiplatelet - -
Antiplatelet drugs: classification
 Drugs that reduce platelet activation:
 Inhibit thronboxane A2 production
 Aspirin
 Incraese cAMP levels
 Clopidogrel
 Dipyridamol
 Drugs that reduce platelet aggregation
 Block glycoprotein GP IIb/IIIa
 Abciximab
 Aspirin
 Irreversibly inhibits platelet COX-1 and COX-2
and blocks the production of thromboxane A2.
 Inhibits platelet:
 activation
 aggregation
 Aspirin produces antiplatelet effect in low dose
75mg once daily. Anti-inflammatory dose is 4g
daily.

Explain why other NSAIDs are not used as

antiplatelet drugs
 platelet
ADP-receptor blocker
Mechanism of action
Platelet
Activation
ADP receptor ADP Clopid
ogrel
(P2Y12)
platelet
Platelet Gi -
protein
membrane

Adenylate Cyclase

Dipyri
damol
Ca++ Platelet
ATP cAMP
Aggregation
-
Phosphodiesterase
5’ AMP
 Clopidogrel and Dipyridamole

Clopidogrel Dipyridamole

 MOA: Non-competitive  MOA: Lowers platelet calcium

ADP (P2Y12) G-protein- and increases accumulation of
coupled receptors blockers. cAMP, coronary vasodilator.
Causes irreversible
blockade  Oral administration
 Oral administration  Headache, hypersensitivity,
 GI reactions, bleeding
hypersensitivity, bleeding
GP IIb/IIIa inhibtor
GP IIb/IIIa

The Glycoprotein IIb/IIIa (GP IIb/IIIa) platelet membrane receptor is

G-protein-coupled receptor.
GP IIb/IIIa is a binding site for fibrinogen to link activated platelets.
Glycoprotein (GP) IIb/IIIa
blockers
─ Abciximab
 Abciximab is monoclonal antibody
against GP IIb/IIIa
 Abciximab blocks the final common
pathway of platelet aggregation.
 Only parenteral (IV) administration.
 ADRs:
 Thrombocytopenia
 Bleeding
Antiplatelet Drugs
Therapeutic uses
 Treatment of acute thrombosis:
 ACS (STEMI + NSTEMI + Unstable
Angina)
 Ischemic stroke
 Prevention of thrombosis in patients:
 with cardiovascular risk factors
 after cardiac surgery and stenting
 arrhythmias (atrial fibrillation)
 Thrombolytics

Vascular injury

Platelet adherence Antiplatelets

activation

Thrombin and fibrin Anticoagulants

generation

Fibrinolysis Thrombolytics
Fibrinolytic (Thrombolytic)
system
TISSUE PLASMINOGEN ACTIVATOR (tPA)

PLASMINOGEN PLASMIN

FIBRIN
FIBRIN DEGRADATION
PRODUCTS
Thrombolytics
Classification

 Indirect plasminogen activator

─ Streptokinase

 Tissue plasminogen activator (tPA)

and recombinant tPA
─ Alteplase
 Streptokinase
Mechanism of action
STREPTOKINASE PLASMINOGEN • Bacterial
protein (β-
haemolytic
streptococci)
• Indirectly
activates free
PLASMINOGEN PLASMIN and bounded
plasminogen
• Also inhibits
FIBRIN fibrinogen and
FIBRIN DEGRADATION V, VII
PRODUCTS coagulation
factors.

Streptokinase
is not co-
administered
with heparin!
 Alteplase
Mechanism of action

ALTEPLASE • Recombinant
tissue
plasminogen
activator (r-
tPA)
• Selectively
activates
CLOT-SPECIFIC PLASMIN plasminogen
PLASMINOGEN bound to fibrin
(clot-specific).
• No
anticoagulation
FIBRIN effect.
FIBRIN DEGRADATION
PRODUCTS
Thrombolytics
Indications
 Are used only in the treatment of
thrombosis in case of:
 ST elevation Myocardial infarction
Thrombolytics are effective only during
first 12 hours of STEMI
 Ischemic stroke
 Pulmonary embolism
 Deep vein thrombosis
Thrombolytics are never used for the
prevention of thrombosis
Antiplatelet and Thrombolytics: adverse
effects and Contraindications

Contraindications
Bleeding is the most  Active bleeding
severe ADR  Haemorrhagic disorders
(hemophilia,thrombocyto
penia, etc.)
 Aortic dissection
 Recent surgery
 Acute pancreatitis
 Haemorrhagic stroke
 Intracranial neoplasm
 Pregnancy
 Antocoagulants

Vascular injury

Platelet adherence Antiplatelets

activation

Thrombin and fibrin Anticoagulants

generation

Fibrinolysis Thrombolytics
Coagulation pathways

Normal endothelium
Prostacycline
Protein C
Antithrombin
12 to 14 seconds
26 to 33 seconds

Inhibits coagulation
factors
of intrinsic and
common pathways
Anticoagulants
PARENTERAL
 Heparin (Unfractionated heparin (UFH)
(Mol wt ≈ 15000 Dalton).
 Heparin derivatives
 Low molecular weight heparin (LMWH). (Mol
wt ≈ 5000 Dalton): Enoxaparin
 Fondaparinux (Synthetic) (Mol wt ≈ 1500
Dalton)
 Lepuridin
ORAL
Heparin/LMWH: MOA
Fondaparinux
 Synthetic pentasaccharide
 Action similar to LMWH.

Fondaparinux: the pentasaccharide unit

Inactivates factor Xa only

Pharmacokinetics
 Heparin, LMWH, Fondaparinux (FPN)
 No oral absorption.
 Heparin: IV or subcutaneous injection.
 LMWH and FPN: SC
 Rapid onset of action
 Half-life: Heparin<LMWH<FPN
 LMWH and FPN undergo unchanged renal
excretion
 Heparin: Dose-dependent half-life.
 LMWH/FPN: t1/2 is not dose-dependent.
Clearance of LMWH versus UFH
LMWH/FPN  Heparin:
monitoring
by aPTT.

 LMWH/FPN:
aPTT
monitoring
LMWH/FPN:
not
• Better pharmacokinetic profile. required.
• More predictable dose-response.
• More favorable benefit-risk ratio.
Heparin: adverse effects

 Most common: Bleeding

Advantages of LMWH/FPN over UFH
Predictable PK profile .. Can be given in OPD.
Monitoring not required.
Low incidence of bleeding/HIT.

Can you
• Protamine sulfate is thethink
antidote for heparin.
• Binds tightlyof a few
with heparin and neutralizes its
action. contraindications?
• It is used to reverse the action of heparin in
cases of overdose.
Heparin-induced
thrombocytopenia
Not common but Serious
More likely with UFH than with LMWH/FPN. Treated by
direct thrombin inhibitors.
 Direct thrombin inhibitors
 Directly bind to the active site of thrombin: Specific,
irreversible thrombin inhibitor
 Lepuridin
 Can also inactivate thrombin inside the clot/thrombi.
 Is given by IV route, monitored by the aPTT.
 Used to treat HIT-related thrombosis.
Oral antocoagulants
 Vitamin K antagonist
 Warfarin
 NOAC (Non-vit K oral anticoagulants/
Novel anticoagulants)/TSOAC (Target
specific oral anticoagulants)/DOAC
(Direct oral anticoagulants)
 Direct thrombin inhibitor: Dabigatran
 Direct Factor Xa inhibitor: Rivaroxaban
Warfarin and coumarin
anticoagulants
 The name warfarin is derived from
the name of the patent holder,
Wisconsin Alumni Research
Foundation and arin from coumarin.
 Were initially used as rodenticides.
 Introduced for human use in 1950s.
 Warfarin is now one of the most
commonly prescribed drugs.
 Warfarin: mechanism of action
Activated

A ctiv
×
at ion
coagulation
factors ×
COAGULATION
Inactivate
coagulation
factors

Vitamin K
(Oxidized)
Vitamin K
(Reduced)
c tas e
du

Vit am in K
e po
×x id e re

WARFARIN
 Oral anticoagulants: effects

 Blocks new synthesis of

activated coagulation
factors (II, VII, IX and
X).
 No effect on the
activity of active
coagulation factors
already in the
circulation.
 Action of warfarin
Peak anticoagulant
appears only when such
effect may be delayed
molecules disappear from
by 72 to 96 hours
circulation.
Warfarin: PK
 Administered orally
 Complete bioavailability.
 99% plasma protein bound.
 Metabolized by cytochrome enzymes.

Drug-drug interactions

Warfarin with erythromycin

Warfarin with rifampicin
Warfarin with vitamin K rich food
Warfarin with sulfonamides
 Warfarin therapy: monitoring

 Warfarin therapy is monitored by

measuring PT.
• Most common: BLEEDING
• Rare but serious: Thrombotic
complications like tissue necrosis.
• Absolute contraindication: pregnancy
– birth defects, Fetal or neonatal hemorrhage
and intrauterine death.
– Other contraindications??

Antidote is vitamin K
Dabigatran

 Highly specific and competitive direct

thrombin inhibitor.
 Orally administration.
 Rapid onset of action (1–2 h),
 80% renal excretion
 No major drug–food interactions.
 No monitoring required.
Rivaroxaban

 Competitive and direct inhibitor of

factor Xa.
 Onset of action: 2-4 hours
 35% renal clearance
 No drug-food interactions.
 No monitoring required.
Anticoagulants: therapeutic uses

 Thromboembolism
 Prevention and treatment of venous thrombosis
and pulmonary embolism (atrial fibrillation).
 Prophylaxis in high-risk patients.
 NOAC: Treatment and prevention of stroke and
systemic embolism in patients with Non
valvular AF, VTE, PE
 valvular AF, VTE, PE: warfarin
 Impaired renal function?????????
 Early stages of unstable angina and MI.
Heparin is the drug of choice for
anticoagulation during pregnancy.
 NOACs

 Contraindications:
 Renal impairment
 Patients at high risk of bleeding (GI)
 Hypersensitivity to drug
 Drug-drug interaction :ketoconazole,
rifampicin, phenytoin etc
 Management of ACS

1. Pain relive:
 Opioid analgesics (Morphine, Fentanyl)
2. Reperfusion of ischemic area:
 Angioplasty
 Thrombolytics
3. Prevention of further thrombosis:
 Antiplatelets
 Anticoagulants
4. Antianginal drugs:
 Nitrates
 Beta-blockers
 Management of ACS
STEMI NSTEMI + Unstable
Angina

1. Pain relive:
- Morphine + +
2. Reperfusion of
ischemic area: + ─
-Thrombolytics

3. Prevention of further
thrombosis: + +
- Antiplatelets
- Anticoagulants

4. Antianginal drugs:
- Nitrates + +
- Beta-blockers

What about venous thromboembolism?

Which is the most appropriate
anticoagulant?

Heparin
or warfarin??
 Anticoagulants: therapeutic use
A patient with rheumatic heart valve disease
was assessed to be on immediate risk of
TE. To start the anticoagulant therapy
which one is the most appropriate
option:

a. Warfarin
b. Rivaroxban
c. Dabigatran
d. Heparin
While starting this patient on
warfarin, which approach is most
suitable?

a. Start oral warfarin and continue the

same.
b. Start with IV heparin + oral warfarin,
continue with warfarin alone after 10
days.
c. Start with heparin sc, stop heparin and
start warfarin 10 days later.
 A patient with myocardial infarction
was administered with an antiplatelet
drug that requires parenteral
administration.
 Which is the most likely drug
administered to the patient?
 Aspirin
 Clopidogrel
 Dipyridamol
 Abciximab
• A 45 year old woman was treated with
warfarin for deep vein thrombosis.
Recently she was found to have
impaired liver functions. The patient
required a reduction in the dose of
warfarin.
Why?
1. Warfarin metabolism will slow down in
this patient
2. Warfarin absorption will be faster in this
patient.
3. Renal clearance of warfarin will be
slower in this patient.
4. Protein binding of warfarin will increase
in this patient
Thank you!