Drugs used in haematology;

anticoagulants, antiplatelet agents and

thrombolytic agents

Dr Clare Guilding
e.mail: clare.guilding@ncl.ac.uk
Drugs used in haematology

Learning Outcomes
This session should assist you in acquiring the knowledge &
understanding to:
― Describe the basic pharmacology of anticoagulant, antiplatelet
and fibrinolytic drugs

Lesson outline
1. Disorders of inappropriate blood clotting (thrombosis)
2. Drugs developed to prevent and/or reverse thrombus
formation:
- Anticoagulants
- Antiplatelet agents
- Thrombolytic agents
Drugs and blood clotting

Before you learn the pharmacology of anticoagulant drugs you

should ensure you understand the following physiological
processes:

• Normal haemostatic processes

1. Vasoconstriction – reduces blood flow therefore reduces
blood loss
2. Platelet plug formation – involving platelet adhesion,
platelet release reaction and platelet aggregation
3. Stable clot formation (coagulation cascade) – end result is
activation of thrombin which :
a) converts soluble fibrinogen to insoluble fibrin
b) induces more platelet recruitment and activation

• Normal fibrinolytic mechanisms

Thrombosis

• Thrombosis – pathogenic state in which the normal

haemostatic processes are activated inappropriately

Atrial Fibrillation
Deep Vein Thrombosis
Pulmonary Embolus
Myocardial infarction
Thrombosis

• Thrombosis – pathogenic state in which the normal

haemostatic processes are activated inappropriately

Atrial Fibrillation
Deep Vein Thrombosis Anticoagulants
Pulmonary Embolus Antiplatelet agents
Myocardial infarction Fibrinolytic agents
Formation of thrombus

• Thrombus - a blood clot formed in vivo

- has a distinct structure – white head, red tail

There are 2 main types of thrombus:

1. Arterial thrombus
2. Venous thrombus Tissue
factor

Collagen

Smooth
muscle
Subendothelial
Endothelium matrix
Adapted from© Can Stock Photo / rob3000
Formation of thrombus
1. Arterial thrombus:
— Thrombus has large head, formed from platelets
— Primary trigger of arterial thrombosis is rupture of an
atherosclerotic plaque (seen in yellow)
Vessel wall
Endothelium
Thrombus in the lumen of a
Thrombus coronary artery
Rupture of plaque

Atheroscleroti
c plaque

Necrotic core Foam cells

Adapted from © Can Stock Photo / megija

— Mainly treated with antiplatelet drugs

Formation of thrombus

2. Venous thrombus:
— Thrombus consists of a fibrin web enmeshed with red
blood cells and platelets
— Tail can break off giving rise to embolisms
A thromboembolus filling a
Abnormal
blood flow pulmonary artery

Altered
vessel wall Increased
coagulability erythrocytes

Adapted from © Can Stock Photo / alila

— Mainly treated with anticoagulant drugs

Drugs and blood clotting

• Drugs have been developed to prevent and/or reverse thrombus

formation. These drugs fall into 3 classes:

1. Anticoagulants
e.g Heparin and oral anticoagulants
- modify blood clotting mechanisms

2. Antiplatelet agents
e.g Aspirin include clopidrogel next year
- inhibit COX-1 activity to inhibit platelet aggregation

3. Fibrinolytic agents
e.g Alteplase
- break down fibrin
Anticoagulants

• There are 4 main classes of anticoagulant

1. Heparin and low molecular weight heparins

2. Warfarin
3. Selective factor Xa inhibitors
4. Direct thrombin (factor IIa) inhibitors

• Anticoagulants target various factors in the coagulation cascade,

thereby preventing formation of a stable fibrin meshwork.
Heparin

Pharmacodynamics

• Family of sulphated mucopolysaccharides, found in the

secretory granules of mast cells
• Commercial preparations vary in MW from 3000 to 30,000Da

• Inhibits coagulation by activating antithrombin III (AT III)

 AT III is a naturally occurring inhibitor of thrombin and clotting

factors IX, Xa, XI and XII
 In the presence of heparin, AT III becomes ~1000x more active
and inhibition of clotting factors is instantaneous
Blood clotting cascade
Extrinsic pathway Intrinsic pathway

Tissue damage Contact

VII VIIa XIIa XII

XIa XI

IXa IX

X Xa

XIII
II (Prothrombin) IIa (Thrombin)
XIIIa

Fibrinogen Fibrin Stabilised fibrin

Blood clotting cascade
Extrinsic pathway Intrinsic pathway

Tissue damage Contact

Heparin
VII VIIa XIIa XII
AT III
Heparin
XIa XI
AT III
Heparin
IXa IX
AT III

Heparin
X Xa
AT III
XIII
Heparin
II (Prothrombin) IIa (Thrombin)
AT III
XIIIa

Fibrinogen Fibrin Stabilised fibrin

Low molecular weight heparins (LMWH)

Pharmacodynamics

• Low molecular weight heparins (LMWH; fragments or

synthetic heparin) have more consistent activity
e.g. enoxaparin*

• LMWHs inactivate factor Xa (and thrombin) (also via

activation of antithrombin III)

• Heparin and LMWH have immediate onset of action

Blood clotting cascade
Extrinsic pathway Intrinsic pathway

Contact
Tissue damage (e.g. with glass)

VII VIIa XIIa XII

XIa XI

IXa IX

LMWH
X Xa
ATIII
XIII
II (Prothrombin) IIa (Thrombin)
XIIIa

Fibrinogen Fibrin Stabilised fibrin

Heparin and LMWH: Pharmacokinetics

• Inactive given orally (not absorbed from GI tract)

• Administered IV or SC (SC for LMWHs)

• Heparin has a short half life (t ½ <1h low doses, 2h large doses)
― Heparin must be given frequently or as a continuous
infusion

• LMWH have longer duration of action (t ½ ~4-5h)

― Allows once daily dosing

• Eliminated mainly by renal excretion

― Care needed in patients with renal disease

• Side effects include bleeding and hypersensitivity

• Overdose treated by IV protamine (strongly basic protein)

Heparin: Clinical use

• Treatment of established venous thromboembolism

• Prevention of venous thromboembolism – LMWHs used to

prevent post-operative venous thrombosis

• Cardiac disease – reduces risk of venous thromboembolism in

patients with angina and following acute MI

Because of the need for frequent dosing, if long-term

anticoagulation is required, heparin is often used only to commence
anticoagulation therapy until an oral anticoagulant takes effect
Oral anticoagulants: Vitamin K cycle

Inactive clotting factors Active clotting factors

Inactive clotting II, VII, IX, X IIa, VIIa, IXa, Xa
factors can’t bind
stably to the blood
vessel
endothelium and
cannot activate
clotting

• Vitamin K levels in humans are maintained by the action of the

enzyme Vitamin K reductase which ‘recycles’ Vitamin K

• Vitamin K is required to activate the clotting factors II, VII, IX, X

Oral anticoagulants: Mechanism of action

Inactive clotting factors

Inactive clotting II, VII, IX, X
factors can’t bind
stably to the blood
vessel
endothelium and
cannot activate
clotting

 Warfarin inhibits Vitamin K reductase thus prevents the

activation of the clotting factors II, VII, IX, X
Blood clotting and warfarin
Extrinsic pathway Intrinsic pathway

Tissue damage Contact

VII VIIa XIIa XII

XIa XI

IXa IX

X Xa

XIII
II (Prothrombin) IIa (Thrombin)
XIIIa

Fibrinogen Fibrin Stabilised fibrin

Blood clotting and warfarin
Extrinsic pathway Intrinsic pathway

Tissue damage Contact

VII W VIIa XIIa XII

XIa XI

IXa W IX

X W Xa

XIII
II (Prothrombin) W IIa (Thrombin)
XIIIa

Fibrinogen Fibrin Stabilised fibrin

Warfarin: Pharmacodynamics and pharmacokinetics

• Inhibits the activation of Vitamin K1 dependent clotting factors

II, VII, IX and X

• The shift in haemostatic balance in favour of anticoagulation

doesn’t take place until all active vitamin K dependant proteins,
made before the drug was administered have been cleared
from the circulation.

• The process occurs at different rates for different clotting

factors e.g. half life VII ~6h, half life IX and X 9 ~ 8-24h, half life
prothrombin (II) ~72h
 Hence there is a 1-2 day lag period before warfarin is
pharmacologically effective

• A small population of patients is genetically resistant to

warfarin, due to reduced binding to Vitamin K reductases
Warfarin: Pharmacokinetics

• Absorption - rapidly and almost totally absorbed from the GI

tract
- levels peak in blood ~0.5-4h after administration

• Distribution – low volume of distribution as ~ 99% plasma

protein bound (mainly to albumin)

• Metabolism – action is terminated by metabolism in the liver

by CYP450 enzymes (e.g. CYP2C9, 2C19, 3A4)

• Excretion – metabolites are conjugated to glucuronide and

excreted in urine and faeces

• Half life – variable ~ 15-80 hours

• Dose is highly variable - (2-112 mg/week)

Warfarin: Clinical use

• To prevent the progression or

reoccurrence of:
— Venous thrombosis
— Pulmonary embolus

• To prevent:
— Arterial thromboemboli in
patients with atrial
fibrillation or cardiac
disease (including
mechanical heart valves)

• At least 6 weeks anticoagulation is recommended for calf

vein thrombosis and at least 3 months for DVT or PE
Clinical practice

• Acute anticoagulation usually starts with heparin and an

oral anticoagulant e.g. warfarin

• Heparin is rapidly effective

– Effect of heparin is monitored by activated partial
thromboplastin time (APTT)
– LMMH – usually no monitoring needed, has less side
effects and fewer bleeding complications

• Warfarin takes several days to achieve full anticoagulation

– Effect of anticoagulant monitored using the prothrombin
time (converted to INR: International normalised ratio)

• Heparin therefore covers the lag period and can then be

withdrawn
Warfarin prescribing questions

Your patient is prescribed warfarin. Would the addition of the

following drugs to the dosing regimen increase or decrease
anticoagulation within the body?

1. Drugs which have a high affinity for the plasma binding

protein albumin e.g. sulfonamides

2. Drugs which reduce absorption e.g. sucralfate

3. Drugs which decrease platelet aggregation e.g. aspirin

4. Drugs which inhibit CYP 2C9 e.g. St John’s Wort

Warfarin prescribing questions

Your patient is prescribed warfarin. Would the addition of the

following drugs to the dosing regimen increase or decrease
anticoagulation within the body?

1. Drugs which have a high affinity for the plasma binding

protein albumin e.g. sulfonamides
Increase. Warfarin is highly plasma protein bound. Sulfonamides
comptete with warfarin for binging to albumin, so more warfarin
is free/unbound (=more pharmacologically available)

2. Drugs which reduce absorption e.g. sucralfate

3. Drugs which decrease platelet aggregation e.g. aspirin

4. Drugs which inhibit CYP 2C9 e.g. St John’s Wort

Warfarin prescribing questions

Your patient is prescribed warfarin. Would the addition of the

following drugs to the dosing regimen increase or decrease
anticoagulation within the body?

1. Drugs which have a high affinity for the plasma binding

protein albumin e.g. sulfonamides

2. Drugs which reduce absorption e.g. sucralfate

Decrease. Less warfarin would be absorbed from the GI tract

3. Drugs which decrease platelet aggregation e.g. aspirin

4. Drugs which inhibit CYP 2C9 e.g. St John’s Wort

Warfarin prescribing questions

Your patient is prescribed warfarin. Would the addition of the

following drugs to the dosing regimen increase or decrease
anticoagulation within the body?

1. Drugs which have a high affinity for the plasma binding

protein albumin e.g. sulfonamides

2. Drugs which reduce absorption e.g. sucralfate

3. Drugs which decrease platelet aggregation e.g. aspirin

Increase. Both drugs ultimately lead to a reduction in blood clot
formation, so addition of aspirin would potentiate warfarin’s
actions

4. Drugs which inhibit CYP 2C9 e.g. St John’s Wort

Warfarin prescribing questions

Your patient is prescribed warfarin. Would the addition of the

following drugs to the dosing regimen increase or decrease
anticoagulation within the body?

1. Drugs which have a high affinity for the plasma binding

protein albumin e.g. sulfonamides

2. Drugs which reduce absorption e.g. sucralfate

3. Drugs which decrease platelet aggregation e.g. aspirin

4. Drugs which inhibit CYP 2C9 e.g. St John’s Wort

Increase. CYP2C9 metabolises (inactivates) warfarin. Less CYP2C9
= less inactivation = more pharmacologically active warfarin
remains
Newer oral anticoagulants

3. Selective factor Xa inhibitors

4. Direct thrombin (factor IIa) inhibitors e.g. dabigatran

Dabigatran
• Competitive reversible inhibitor of thrombin
• Used for:
— Prevention of stroke and embolism in patients with
atrial fibrillation
— Prophylaxis of venous thromboembolism after hip or
knee replacement surgery
• Has a rapid onset of action
• Does NOT require routine oral anticoagulant monitoring
• No way to reverse anticoagulation in the event of a
significant bleed
Direct thrombin (factor IIa) inhibitors
Extrinsic pathway Intrinsic pathway

Tissue damage Contact

VII VIIa XIIa XII

XIa XI

IXa IX

X Xa

XIII
II (Prothrombin) IIa (Thrombin)
XIIIa

Fibrinogen Fibrin Stabilised fibrin

Direct thrombin (factor IIa) inhibitors
Extrinsic pathway Intrinsic pathway

Tissue damage Contact

VII VIIa XIIa XII

XIa XI

IXa IX

X Xa

XIII
II (Prothrombin) Dabigatran
IIa (Thrombin)

XIIIa

Fibrinogen Fibrin Stabilised fibrin

Drugs and blood clotting

Lesson outline

1. Disorders of inappropriate blood clotting (thrombosis)

2. Drugs developed to prevent and/or reverse thrombus
formation:
- Anticoagulants
- Antiplatelet agents
- Thrombolytic agents
Antiplatelet drugs

• Platelets provide the initial haemostatic plug at sites of vascular

injury
 Inhibition of platelet function is a useful prophylactic and
therapeutic strategy against MI and stroke caused by thrombosis

2 3

From Lippincott's Illustrated Review Pharmacology

Antiplatelet drugs e.g. aspirin
• Platelet-derived thromboxane A2 (TXA2) promotes aggregation

Recruits platelets into plug

Antiplatelet drugs e.g. aspirin

• Aspirin irreversibly inhibits COX-1, therefore inhibits the

synthesis of TXA2
• Because platelets do not contain DNA or RNA they cannot
cannot synthesise new COX-1
• The inhibition is irreversible and effective for the life of the
circulating platelet (7-10 days)

Clinical use:

x x
Used prophylactically to prevent
arterial thrombosis leading to:
– transient ischemic attack
– stroke
– myocardial infarction
x
Fibrinolytic (thrombolytic) drugs e.g. streptokinase, alteplase
• Thromboses are dynamic - balance between breakdown
(fibrinolysis) and formation
• Thrombolytic drugs potentiate the effects of the fibrinolytic
system
• They activate conversion of plasminogen to plasmin which
breaks down fibrin, thus dissolves clots

Fibrinolysis
Fibrinolytic (thrombolytic) drugs e.g. streptokinase, alteplase

• Administered iv; immediate effect

• Short half-lives (<10-90 mins)
• Main hazard is bleeding
• Main uses nowadays:
— restoring catheter and shunt function,
by lysing clots causing occlusions
— To dissolve clots that result in strokes
Key points
Think back through the presentation and write some of the key
points you have learned in your own words

• …

• …

• …

• …
Key points

• Heparin works by activating antithrombin III, a naturally

occurring inhibitor of clotting factors

• Warfarin works by inhibiting vitamin K reductase

• Heparin is immediately effective, warfarin can take 1-2 days to

be effective

• Heparin must be administered parenterally, warfarin orally

• Thrombolytic agents stimulate fibrinolysis by activating

conversion of plasminogen to plasmin (which breaks down fibrin)

• Aspirin inhibits COX mediated production of TXA2 , inhibiting

TXA2 mediated platelet aggregation
Recommended reading

Rang, Dale, Ritter and Flower. Pharmacology.

Relevant sections within the chapter ‘Haemostasis and
thrombosis’.

Golan et al. Principles of Pharmacology.

Relevant sections within the chapter ‘Pharmacology of
Haemostasis and Thrombosis’.

Additional images come from Lippincott's Illustrated Review

Pharmacology