Drugs affecting blood coagulation, platelet aggregation and thrombosis

Question 1

What factor number is prothrombin?

And thrombin?

Answer 1

Prothrombin - Factor II

Thrombin - Factor IIa

Question 2

Which factor stabilises fibrin?

Answer 2

Factor XIIIa

Question 3

Which endogenous chemicals suppress platelet activation?

Answer 3

Thromboxane A2
Adrenaline
ATP
5-HT (serotonin)

Question 4

Define thrombosis

Answer 4

Formation of a clot (thrombus) inside an entact blood vessel (therefore no need for it)

Question 5

what is an egotheromatous plaque?

Answer 5

Plaques caused by endothelial damage

Question 6

Name three general mechanisms of how to prevent clots

Answer 6

Target coagulation
Target platelet activation
Promote fibrinolysis

Question 7

Targeting coagulation is more effective in which type of thrombosis?
Classes of drugs to help?

Answer 7

Venous thrombosis
Parenteral anticoagulants
Oral anticoagulants

Question 8

Name some parenteral anticoagulant drug classes

Answer 8

Heparin

Hirudins

Question 9

Classes of oral anticoagulant drugs

Answer 9

Warfarin
Thrombin inhibitors
Factor Xa inhibitors

Question 10

Heparins are what kind of biomolecule?
Where do they occur naturally, if at all?
How do they act?
2 size ranges

Answer 10

Micropolysaccharides
Occur naturally, made by endothelium, mast cells and basophils
Inhibits thrombin, factor Xa and factor IXa
2 types:
-Unfractioned - >/= 18 sugar units (preferred for patients with renal failure)
-Low molecular weight heparins >/=5 sugar units

Question 11

Fondaparinux

Answer 11

Same mechanism as thrombin
Acts via antithombin III (endogenous inhibitor of coagulation), forms inactive complex with thrombin, factor IXa, factor Xa

Question 12

How does Heparin work

Answer 12

-Acts on all of cascade - intrinsic, extrinisic and common pathways
-Inhibits factors XII, XI, IX, VIII, Thrombin (IIa)
-increases rate of formation of antithrombin III complexes 1000 fold
-to block thrombin, heparin must bind both ATIII and thrombin
-Heparin increases the formation of the factor Xa/ATIII complex WITHOUT binding factor Xa
-Blocks factor IXa from activating factor X, hence prevents factor II (prothrombin) from becoming thrombin (factor IIa)
Therefore prevents platelet activation

Question 13

LMW heparins affect what

Answer 13

LMW heparins are shorter and affect factor Xa but not thrombin

Question 14

Heparin problems

Answer 14

Risk of haemorrhage:

• mild - cease administration
• severe - inactivate heparin using protamine (forms inactive complex but is only partially effective against LMW heparin)
• HIT (heparin-induced thrombocytopaenia)

Question 15

What is heparin-induced thrombocytopaenia?

Answer 15

Type I - direct effect of heparin (causes clumpng)

Type II - heparin induces formation of antibodies that bind to platelets - serious! Discontinue use

Question 16

What heparin doesn’t cause HIT?

Answer 16

The heparinoid drug Denapanoid
Related to LMW Heparin
Safe alternative

Question 17

How how hirudins work?

Answer 17

block/inhibit factor IIa (thrombin)

Question 18

Bivalirudin use

Answer 18

Hirudin analogue used in unstable angina and some MI patients

Question 19

Carboxylation of which clotting factors is essential to their function?
What kind of modification is this?
What does this process require?

Answer 19

II, VII, IX and X
Post-translational modification

Process requires enzymes that need vitamin K to function. Vitamin K is oxidised in the reaction.
For continued function, the oxidised vitamin K must be reduced by Vitamin-K reductase

Question 20

How does warfarin work?

Answer 20

Completely inhibits the enzyme vitamin K reductase
Therefore reduces clotting factor maturation (II, VII, IX, X)
Anticoagulant effect

Question 21

Why doees warfarin have a slow onset?

Answer 21

Need for pre-existing clotting factors to become depleted

Question 22

In what circumstances do you give warfarin and for how long?

Answer 22

1st DVT/pulmonary embolism - give for 3 months

2nd - give lifelong

Question 23

Warfarin overdose treatment

Answer 23

Vitamin K

Question 24

effect of warfarin on microorganisms in gut

Answer 24

MOs make vitamin K - antibiotics may affect warfarin efficacy

Question 25

Side effects of warfarin and interactions

Answer 25

Haemorrhage common (nase, pharynx, GI tract, urinary tract) - mild - stop administation - severe - give vitamin K, purified clotting factors and whole blood Skin necrosis Avoid in pregnancy as a tetrogen, crosses placenta and can cause haemorrhage in neonates Notorious for drug interactions, induction/inhibition by other drugs as CYP450 Need for regular monitoring - INR, blood coagulation test

Question 26

How thrombin inhibitors work When are they given? Common side effect?

Answer 26

``` oral anticoagulants Not widely used -Block action of thrombin -or block action of factor Xa Given after joint replacement, Haemorrhage common unwanted effect ```

Question 27

Which drug blocks action of Thrombin

Answer 27

dabigatran

Question 28

Which 2 drugs block action of factor Xa

Answer 28

Apixaban | Rivaroxaban

Question 29

PGI2 effect on platelet aggregation | And what about Thromboxane A2?

Answer 29

PGI2 reduces platelet aggregation by ↑cAMP Thromboxane A2 ↑platelet aggregation by ↓cAMP Note: Atheromaous plaques release PGI2

Question 30

Aspirin as an anticoagulant How does it work? Low dose effects High dose effects

Answer 30

Blocks COX enzyme Platelets cannot make new COX as they have no nuclei TXA2 production and platelet aggregation blocked until new platelets are produced Endothelial cells can produce more COX so PGI2 production is spared Low dose - affect platelets High dose - reduced PGI2 production by endothelium, therefore more risk of platelet aggregation

Question 31

Epoprostenol What does it do? How and when is it given?

Answer 31

Prostacyclin (PGI2) agonist antiplatelet therapy Mimics effects of prostacyclin therefore reduces platelet aggregaton by ↑cAMP Given by IV infusion (unstable) during haemodialysis and for pulmonary hypertension Powerful vasodilator therefore has adverse effects

Question 32

Dipyramidamole action

Answer 32

Blocks PDE so reduced cAMP breakdown so ↑cAMP | but also inhibits TxA2 synthesis and ADP production