L9 Prevention and treatment of thrombosis antiplatelets, anticoagulants, thrombolytics

rupture of the atherosclerotic plaque in the artery causes adhesion, activation and aggregation of platelets which increases exposure of acidic phospholipids and… (platelet reactions)

creates secretion of performed mediators (e.g. ADP) and synthesis of mediators (e.g. TXA2 and PAF)

• causes further aggregation of platelets and the formation of a thrombus

rupture of the atherosclerotic plaque in the artery causes (coagulation pathway)

in vivo pathway (tissue factor and factor VIIa) and direct contact pathway factors (XII and XI)

• these cause factor X to form Xa

• Xa forms II which converts to thrombin

• Thrombin converts fibrinogen to fibrin

• fibrin causes a thrombus

what are the 3 drugs used to prevent/reverse thrombin formation

• anticoagulants

• antiplatelet agents

• fibrinolytic agents

describe anticoagulants as a thrombus prevention drug

Factor Xa inhibitors, Antithrombins, Heparin, Vit K antagonists

• modify blood clotting mechanisms-stop clots forming

describe antiplatelet agents as a thrombus prevention drug

Aspirin

• inhibits COX-1 activity to inhibit platelet aggregation

• good at preventing arterial blood clots (from atherosclerotic plaque)

• stops further blood clots forming- the second clot can be the killer

describe fibrinolytic agents as a thrombus reverse drug

Alteplase

• breaks down fibrin

• don’t prevent clots forming, but causes the clot already there to dissolve

give an example of the class 1 anticoagulant: selective factor Xa inhibitor

Apixaban

• block cascade system

give an example of the class 2 anticoagulant: direct thrombin inhibitors

Dabigatran

• blocks thrombin activation

give an example of the class 3 anticoagulant

heparin and low MW heparins

give an example of the class 4 anticoagulant: vitamin K antagonists

Warfarin

what do anticoagulants do

target various factors in the coagulation cascade, preventing formation of a stable fibrin framework

treatment examples for a venous thromboembolism

Apixaban (direct factor X inhibitors) or rivaroxaban

• confirmed proximal DVT or PE

what is used to treat a venous thromboembolism if apixaban or rivaroxaban are contra-indicated

Low molecular weight heparin (LMWH)

• followed by dabigatran etexilate or edoxaban

LMQH with a vitamin K antagonist

• for 5 days or target INR achieved

• followed by vitamin K antagonist on its own

DVT means

one leg is swollen

• due to vein thromboembolism

Extrinsic pathway of clotting by tissue damage

• Factor VII converts to VIIa which converts X to Xa

• Xa causes prothrombin (II) to form thrombin (IIa)

• Thrombin causes fibrinogen to make fibrin and fibrin to make stabilised fibrin, or

• thrombin converts XIII to XIIIa which causes fibrin to make stabilised fibrin

intrinsic pathway of clotting by contact

• XII makes XIIa

• XIIa converts XI to XIa

• XIa converts IX to IXa

• IXa converts X to Xa

• this causes II prothrombin to make IIa thrombrin which causes either XIII to XIIIa to make stabilised fibrin from fibrin OR converts fibrinogen to fibrin then to stabilised fibrin

give examples of direct acting oral coagulants (DOACs)

• apixaban

• dabigatran etexilate

• edoxaban

• rivaroxaban

what is the mechanism of action of Dabigatran Etexilate as a direct acting oral coagulant (DOAC)

• reversible inhibitor of thrombin

• Idarucizumab reversal agent

what is the mechanism of action of Apixaban, edoxaban and rivaroxaban as direct acting oral coagulants (DOACs)

• reversible inhibitors of activated factor X (Xa) -Andexenant reversible agent

• prevents thrombin generation

• prevents thrombin development

what are the indications for Apixaban, dabigatran etexilate, edoxaban and rivaroxaban as direct acting oral coagulants (DOACs)

• prevention of stroke

• secondary prevention of DVT/PE

what are apixaban, debigatran etexilate and rivaroxaban (DOACs) clinically used for

prevention of venous thromboembolism following surgery

what is rivaroxaban clinically used for

prevention of atherothrombotic events in patients with coronary or peripheral artery disease following an acute myocadial infarction (heart attack)

what are the contra-indications of apixaban?

avoid in conditions with significant risk of bleeding e.g.

• gastrointestinal ulcer

• malignant neoplasms

• oesophageal varices

• elderly

side effects of apixaban

• anaemia

• haemorrhage

apixaban prevents

factor Xa (active form of thrombin)

dabigadran prevents

thrombin IIa

pharmacodynamics of heparin

• sulphated mucopolysaccharide found in secretory granules of mast cells

• commercial preparations vary in MW from 3000 to 30,000Da

• inhibits coagulation by activating antithrombin III (AT III)

Antithrombin III is a

naturally occurring inhibitor of thrombin and clotting factors IX, Xa, XI, XII

in the presence of heparin, antithrombin III becomes ~1000x more active and

inhibition of clotting factors in instantaneous

Low MW heparins examples

• dalteparin sodium

• enoxaparin sodium

• tinzaparin sodium

pharmacodynamics of low MW heparins

more consistent activity than normal heparins

• fragments or synthetic heparin

what do low MW heparins inactivate

factor Xa and thrombin

• also via activation of antithrombin III

heparin and low MW heparins have an

immediate onset of action

heparin and LMWH are administered

by IV or subcutaneously (LMWH)

• inactive given orally- not absorbed from GI tract

Heparin has a short half life (t1/2 <1hour low doses, 2hour large doses) so

it must be given frequently or as a continuous infusion

LMWH have longer duration of action (T1/2 ~4-5hours) which

allows once daily dosing

heparin and LMWH are eliminated by

renal excretion

• care needed in patients with renal disease

side effects of heparin and LMWH are

bleeding and hypersensitivity

• LMWH lower risk of heparin-induced thrombocytopenia

overdose in heparin and LMWH are treated by

IV protamine (strongly basic protein)

give examples of vitamin K antagonists

• warfarin

• acenocoumarol

• phenindione

what do vitamin K antagonists inhibit

the action of vitamin K1 dependent clotting factors II(prothrombin), VII, IX and X

how long to vitamin K antagonists take to cause an anticoagulant effect

48 hours to 72 hours

a small population of patients are genetically resistant to warfarin, due to reduced binding to

Vitamin K reductases

side effects of vitamin K antagonists

haemorrhage and skin necrosis

warfarin targets

INR

patients on warfarin undergo therapeutic drug monitoring because it has a low therapeutic range, warfarin inhibits

vitamin K reductase 1 so vitamin K isnt reduced into hydroquinone and doesnt facilitate the conversion of II,VII,IX,X into gamma-carboxyglutamic acid residues

warfarin absorption

• rapidly and almost completely absorbed from the GI tract

• levels peak in the blood ~0.5-0.4 hours after administration

warfarin distribution

low volume of distribution as ~99% plasma protein is bound (mainly to albumin)

warfarin metabolism

action is terminated by metabolism in the liver by CYP450 enzymes e.g.

• CYP2C9

• CYP219

• CYP3A4

drug drug interactions

warfarin excretion

metabolites are conjugated to glucuronide and excreted in the urine and faeces

half-life of warfarin

15-80 hours

dose of warfarin

variable

• 2-112 mg/week

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