Drugs affecting blood coagulation

Question 1

Thrombosis

Answer 1

Unwanted formation of clots in arterial or venous circulation

Question 2

Venous thrombosis

Answer 2

Associated with stasis of the blood and/or damage to the veins
Clot may become dislodges (embolus) and travel, e.g. pulmonary embolism, cerebrovascular accident
High fibrin content, low platelet content

Question 3

Arterial thrombosis

Answer 3

Thrombus usually forms at site of atherosclerosis, especially after plaque rupture e.g. coronary thrombosis
Low fibrin content, high platelet content (white thrombus)

Question 4

Classification of agents

Answer 4

Anticoagulants and platelet inhibitors prevent thrombus formation (anti-thrombotics)
Fibrinolytic enzymes cause lysis of thombus
Antifibrinolytic drugs promote haemostasis

Question 5

Anticoagulants- parenteral

Answer 5

Unfractionated (standard) heparin
Low molecular weight heparins
Fondaparinux
Bivalirudin
Argatroban

Question 6

Anticoagulants- oral

Answer 6

Warfarin, acenocoumarol and phenindione
Apixaban, edoxaban and rivaroxaban
Dabigatran

Question 7

Heparins

Answer 7

Injectable anticoagulants, active in vivo and in vitro
A family of highly sulphated glycosaminogylcans
Highly negatively charged

Question 8

Unfractionated (standard) heparins

Answer 8

Medical heparin is of animal origin i.e. bovine lung, bovine, porcine or ovine intestinal mucosae
Biological activity stated in units/mL
Action inhibited naturally by heparinases in blood
Protamine sulphate (highly positively charged) is used to bind and inactivate heparin
Heparin-induced thrombocytopenia is a major adverse effect of prolonged treatment, activation, aggregation, then removal of platelets
>5-7 dyas, immune mediated response

Question 9

Unfractionated heparins MOA

Answer 9

UFHs activate and potentiate action of anti-thrombin III leading to the inactivation of thrombin (IIa) and other factrs e.g. Xa

Question 10

Low molecular weight heparins

Answer 10

Obtained by fractionation or depolymerisation of UFHs
LMWHs do not inactivate thrombin but inactivate factor Xa
Dalteparin, enoxaprin, tinzaparin
Fondaparinux is a synthetic pentasaccharide fragment that inactivates factor Xa
Increasingly widely used due to long action (once daily SC injection), less likely than UFHs to induce thrombocytopenia

Question 11

Alternative injectable anticoagulants

Answer 11

Hirudin is a 65-amino acid anticoagulant peptide originally isolated from leech, thrombin factor IIa inhibitor
Bivalirudin is a synthetic peptide derivative, specifically licensed for coronary care setting (e.g. PCI)
Argatraban is a small molecule direct thrombin inhibitor, useful as an alternative to heparin when heparin-induced thrombocytopenia has developed

Question 12

Vitamin K antagonists (coumarins)

Answer 12

Active in vivo only
Inhibit gamma carboxylation of factors II, VII, IX and X by blocking reduction (activation) of K vitamins (menadione derivatives)

Question 13

Examples of coumarins

Answer 13

Warfarin, phenindione, acenocoumarol
Used prophylactically to prevent thrombosis over prolonged periods (including life-long use)
Slow onset, long duration of action
Enormous range of drug interactions which can cause increased or decreased anticoagulant activity

Question 14

Novel oral anticoagulants (NOACs)

Answer 14

Apixaban, edoxaban and rivaroxaban are orally active small direct inhibitors of factor Xa
Dabigatran is an orally active small molecule ihibitor of thrombin (factor IIa), argatroban for IV use only
No routine INR monitoring required
Potential for drug interactions but fewer than with warfarin
Rapid onset, convenient once or twice daily dosing

Question 15

Therapeutic use of anticoagulants

Answer 15

Primarily in management of venous thrombo-embolism but also arterial thrombosis, especially post MI
Injectable anti-coagulants: treatment and prevention of DVT e.g. during hospitalisation for orthopaedic surgery, treatment of pulmonary embolism, post thrombolysis in ACS to prevent arterial re-occlusion, to prevent clotting in extracorporeal circulators
Usually short term although LMWHs may be used chronically

Question 16

Uses of oral anticoagulants

Answer 16

Used for long term (including life-long) prophylactic treatment: prophylaxis against DVT, in atrial fibrillation with stroke risk, prophylaxis after extensive anterior MI
Warfarin requires regular monitoring of INR and dose adjustment (e.g. for change of diet, drugs, alcohol consumption, infection etc.)
NOACs are more convenient, fewer interactions and no INR monitoring but much more expensive

Question 17

Platelet aggregation inhibitors

Answer 17

Target diverse mechanisms of platelet activation (not the protein clotting factors in blood)
Critical role of GPIIb/IIIa expression on platelet surface
Used to inhibit thrombus formation int he arterial rather than venous circulation
Thromboxane synthesis inhibitors
ADP receptor blockers
Glycoprotein IIb/IIIa inhibitors

Question 18

Therapeutic fibrinolytic enzymes

Answer 18

Clinically used agents are naturally occuring or recombinantly-produced plasminogen activators
e.g. streptokinase, alteplase, reteplase, tenecteplase, urokinase
Streptokinase and anistreplase are antigenic- antobody production within 4 days, therefore inactive if given again within 1 year of first administration

Question 19

Major uses of fibrinolytics

Answer 19

Treatment of acute coronary syndromes, especially acute MI
Used as early as possible, some benefit if given up to 12 hours after onset
Heparin and anti-platelet therapy provide additional survival benefit
Percutaneous coronary intervention becoming treatment of choice if available, but not possible in all cases, so fibrinolytics remain a common treatment

Question 20

Other uses of fibrinolytics and major adverse events

Answer 20

Other uses: massive pulmonary embolism, acute ischaemic stroke, DVT
Major adverse events: intracerebral haemorrhage, allergic reaction and anaphylaxis

Question 21

Antifibrinolytic agents (pro-clotting factors)

Answer 21

Act by various mechanisms to reduce fibrinolysis and promote clot formation/ stability
Tranexamic acid: synthetic lysine derivative, inhibits plasminogen activation by reversible blockade of lysine binding sites on plasminogen
Used to prevent or control excessive bleeding e.g. after surgery, dental extraction, thrombolytic overdose, menorrhagia, epistaxis