Drugs and blood clotting

Dr Clare Guildinge.mail: [email protected]

Drugs used in haematology; anticoagulants, antiplatelet agents and thrombolytic agents

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 used in haematology

Drugs and blood clotting

Before you learn the pharmacology of anticoagulant drugs you should ensure you understand the following physiological processes:

• Normal haemostatic processes1. Vasoconstriction – reduces blood flow therefore reduces

blood loss2. Platelet plug formation – involving platelet adhesion,

platelet release reaction and platelet aggregation3. Stable clot formation (coagulation cascade) – end result is

activation of thrombin which :

a) converts soluble fibrinogen to insoluble fibrinb) induces more platelet recruitment and activation

• Normal fibrinolytic mechanisms

Thrombosis

• Thrombosis – pathogenic state in which the normal haemostatic processes are activated inappropriately

Atrial FibrillationDeep Vein Thrombosis

Pulmonary EmbolusMyocardial infarction

Atrial FibrillationDeep Vein Thrombosis

Pulmonary EmbolusMyocardial infarction

AnticoagulantsAntiplatelet agentsFibrinolytic agents

Thrombosis

• Thrombosis – pathogenic state in which the normal haemostatic processes are activated inappropriately

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

Adapted from© Can Stock Photo / rob3000

Tissue factor

Collagen

EndotheliumSubendothelial

matrix

Smooth muscle


1. Arterial thrombus:

— Thrombus has large head, formed from platelets

— Primary trigger of arterial thrombosis is rupture of an atherosclerotic plaque (seen in yellow)

Thrombus in the lumen of a coronary artery

— Mainly treated with antiplatelet drugs

Adapted from © Can Stock Photo / megija

Foam cells

Rupture of plaque

Thrombus

Atherosclerotic plaque

Necrotic core

EndotheliumVessel wall


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 pulmonary artery

— Mainly treated with anticoagulant drugs

Abnormal blood flow

Increased coagulability erythrocytes

Altered vessel wall

Adapted from © Can Stock Photo / alila


• Drugs have been developed to prevent and/or reverse thrombus formation. These drugs fall into 3 classes:

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

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

3. Fibrinolytic agentse.g Alteplase- break down fibrin

Anticoagulants

• There are 4 main classes of anticoagulant

1. Heparin and low molecular weight heparins2. Warfarin3. Selective factor Xa inhibitors4. 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

XIIXIIa

XIXIa

X Xa

IXIXa

II (Prothrombin) IIa (Thrombin)

Fibrinogen Fibrin Stabilised fibrin

XIIIa

XIII

ContactTissue damage

Extrinsic pathway Intrinsic pathway

Blood clotting cascade

VII VIIa

XIIXIIa

XIXIa

X Xa

IXIXa



XIIIa

XIII

Intrinsic pathway

AT III

Heparin

AT III

Heparin

AT III

Heparin

AT III

Heparin

AT III

Heparin


Tissue damage

Extrinsic pathway

VII VIIa

Contact

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

Low molecular weight heparins (LMWH)

XIXIa

X Xa

IXIXa



XIIIa

XIII

Contact(e.g. with glass)

Intrinsic pathway


ATIII

LMWH

Tissue damage

Extrinsic pathway

VII VIIa XIIXIIa

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 factorsII, VII, IX, X

Active clotting factorsIIa, VIIa, IXa, Xa

• 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

Inactive clotting factors can’t bind

stably to the blood vessel

endothelium and cannot activate

clotting

Oral anticoagulants: Mechanism of action

Warfarin inhibits Vitamin K reductase thus prevents the activation of the clotting factors II, VII, IX, X

Inactive clotting factorsII, VII, IX, XInactive clotting

factors can’t bind stably to the blood

vessel endothelium and cannot activate

clotting

XIIXIIa

XIXIa

X Xa

IXIXa



XIIIa

XIII

Tissue damage


VII VIIa

Blood clotting and warfarin

Contact

XIIXIIa

XIXIa

X Xa

IXIXa



XIIIa

XIII

ContactTissue damage


VII VIIa

W

W

W

W

Blood clotting and warfarin

• 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) ~72hHence 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: Pharmacodynamics and 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: Pharmacokinetics

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

• 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

Clinical practice

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



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







2. Drugs which reduce absorption e.g. sucralfateDecrease. Less warfarin would be absorbed from the GI tract







3. Drugs which decrease platelet aggregation e.g. aspirinIncrease. 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 WortIncrease. CYP2C9 metabolises (inactivates) warfarin. Less CYP2C9 = less inactivation = more pharmacologically active warfarin remains


3. Selective factor Xa inhibitors4. Direct thrombin (factor IIa) inhibitors e.g. dabigatran

Newer oral anticoagulants

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

XIIXIIa

XIXIa

X Xa

IXIXa



XIIIa

XIII

Tissue damage


VII VIIa

Direct thrombin (factor IIa) inhibitors

Contact

XIIXIIa

XIXIa

X Xa

IXIXa



XIIIa

XIII

Tissue damage


VII VIIa

Contact

Dabigatran

Direct thrombin (factor IIa) inhibitors


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

1

2 3

From Lippincott's Illustrated Review Pharmacology

Recruits platelets into plug

Antiplatelet drugs e.g. aspirin

• Platelet-derived thromboxane A2 (TXA2) promotes aggregation

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:

Used prophylactically to prevent arterial thrombosis leading to:

– transient ischemic attack

– stroke

– myocardial infarction

xx

x

• Thromboses are dynamic - balance between breakdown (fibrinolysis) and formation

• Thrombolytic drugs potentiate the effects of the fibrinolyticsystem

• They activate conversion of plasminogen to plasmin which breaks down fibrin, thus dissolves clots

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

Fibrinolysis

• 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

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

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 , inhibitingTXA2 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

Education

Drugs and blood clotting