Anticoagulants, Antiplatelets And Thrombolysis

Question 1

Name some indications for Warfarin

Answer 1

PrEvention and treatment of:

DVT (taken for 3-6 months)

PE (taken for 6 months)

After having prosthetic heart valve fitted

Thrombophilia
AF

Question 2

What are the contraindications for Warfarin?

Answer 2

Pregnancy (1st semester teratogenic and 3rd trimester risk of brain haemorrhage)

Peri-op

Haemorrhagic stroke

48 hours post partum

Question 3

Outline the pharmacokinetics for Warfarin

Answer 3

Oral, half life 48 hours, gradual onset (turn over of clotting factors), CYP450 metabolism, variation in dose, action persists after cessation

Question 4

Describe the mechanism of action for Warfarin

Answer 4

Vitamin K is required for the synthesis of clotting factors II (prothrombin), XII, IV, X. In this process vitamin K becomes oxidised and needs to be reduced to be used again. Warfarin competitively inhibits this step reducing the synthesis of vitamin k dependent factors

Question 5

What are the main ADRs of Warfarin?

Answer 5

Haemorrhage, bruising, purpura, teratogenic

Question 6

When might the action of Warfarin be potentiated?

Answer 6

CYP450 inhibitors, antiplatelets, cephalosporin (reduced vitamin k from gut bacteria), protein displacers e.g. NSAIDs

Question 7

When can the action of Warfarin be inhibited?

Answer 7

CYP450 inducers

Question 8

What monitoring is required for Warfarin treatment?

Answer 8

INR, prothrombin time (determines INR), LFT, FBC, give anticoagulant card

Question 9

How would your reverse the action of Warfarin?

Answer 9

Stop Warfarin, antagonism of therapy with IV vitamin K (slow), fresh frozen plasma (fast)

Question 10

What are some indications for heparin?

Answer 10

Prevention of thrombo-embolism e.g. Peri-operative (LMWH) when Warfarin has to be stopped, immobile patients

Treatment of DVT, PE, AF prior to Warfarin (LMWH)

Treatment of MI, angina

Pregnancy when Warfarin can not be used

Question 11

What are some contraindications for heparin?

Answer 11

Haemorrhagic disorder, thrombocytopenia, recent cerebral haemorrhage, severe hypertension, peptic ulcer, trauma

Question 12

What are the differences in pharmacokinetics between unfractionated heparin and low molecular weight heparin?

Answer 12

Unfractionated - IV, non linear, variable bioavailability (binds to cells), requires monitoring, loading dose needed, half life 1-2 hours

Low molecular weight - SC, high bioavailability, more linear, longer half life

Question 13

What is the mechanism for heparin and what is the difference I’m action between unfractionated and low molecular weight?

Answer 13

Heparin binds to antithrombin III and causes a conformational change increasing its activity to increase the inhibition of factors II and Xa

To catalyse Xa inhibition, only antithrombin III has to be bound (achieved by unfractionated and low molecular weight) but to inhibit II heparin needs to bind II and antithrombin III and only unfractionated heparin can do this

Question 14

What are the main ADRs for heparin?

Answer 14

Bleeding - intracranial, injection sites, GI, epistaxis

Bruising

Thrombocytopenia - binds to platelet factor and causes an autoimmune response (less likely with LMW)

Osteoporosis (long term use)

Question 15

What monitoring is required for unfractionated heparin?

Answer 15

Activated partial thromboplastim time (measures the efficacy of the clotting cascade)

Question 16

What is the reversal therapy for heparin?

Answer 16

Protamine sulphate - dissociation of heparin and antithrombin III (irreversibly binds to heparin)

Question 17

When would you use antiplatelets?

Answer 17

Prophylaxis of disorders resulting from intravascular clotting

Question 18

Name 2 antiplatelets that inhibit thromboxane A2 and describe the mechanism for each

Answer 18

Aspirin - inhibits COX enzyme

Dipyridamole - inhibits platelet phosphodiesterase which usually breaks down cAMP, high levels of cAMP inhibits platelet aggregation

Thromboxane A2 is released from activated platelets which causes platelet aggregation and vasoconstriction

Question 19

Name 2 antiplatelets that are ADP receptor antagonists and explain how they work

Answer 19

Clopidogrel, ticlopidine - inhibits ADP dependent aggregation by binding to the P2Y12 receptor where ADP usually binds to a Gi protein to inhibit cAMP thus increased cAMP reduces platelet aggregation.

Question 20

What are GpIIb/III inhibitors and how do they work?

Answer 20

These are antiplatelets used during PCI by inhibiting the receptors on platelets where fibrinogen usually binds to cause aggregation

Question 21

Describe the normal thrombi clearance pathway

Answer 21

Plasminogen binds to fibrin strands within the thrombus and is converted to plasmin by tPA and uPA which cleaves fibrin. This is regulated by circulating factors such as PAI-1

Question 22

What are the indications for thrombolytic therapy?

Answer 22

Acute MI <12 hours - history and ECG

PE

Major venous thrombosis

Ischaemic stroke - if haemorrhage has been ruled out (not recommended due to increased risk of induced cerebral haemorrhage)

Question 23

What are the contraindications for thrombolysis?

Answer 23

Active peptic ulcer, bleeding, recent trauma/surgery, history of cerebral haemorrhage, uncontrolled hypertension, coagulation defect, previously had streptokinase (for streptokinase)

Question 24

What are the two main thrombolytic drugs and how do they work?

Answer 24

Streptokinase - derived from b haemolytic streptococci binds to plasminogen and induces a conformational change to plasmin

Alteplase (recombinant tPA) - acts like the endogenous tPA and works mainly in the presence of fibrin so is clot specific

Question 25

What are they windows of opportunity when treating coronary occlusion, VTE and ischaemic stroke with thrombolysis?

Answer 25

Coronary occlusion - <12 hours

VTE - longer

Ischaemic stroke - <3 hours

Question 26

What are the main ADRs for thrombolytics?

Answer 26

Risk of inducing haemorrhage

Streptokinase - allergic reaction, hypotension, can only be used once (generates antibodies)

Question 27

How would you encourage BP to rise I hypotension induced by thrombolytics?

Answer 27

Slow the IV

Question 28

How would you treat bleeding following thrombolytic therapy?

Answer 28

Blood transfusion, volume expanders, inhibition of fibrinolysis (tranexamic acid, apoprotin, specific recombinant factors, pooled clotting factors)

Question 29

What studies looked at the efficacy of thrombolytics in MI and what did they conclude?

Answer 29

ISIS-3 and GISSI - streptokinase and Alteplase have the same efficacy

Question 30

What study looked at mortality and the use of thrombolytics and what did they conclude?

Answer 30

GUSTO - alteplase achieved slightly greater mortality reduction but increased risk of haemorrhagic stroke

Question 31

Within the first 1-2 hours being treated with thrombolytics for MI, how many deaths per 1000 treated are prevented?

Answer 31

60