Haemostasis and drugs

Question 1

what is haemostasis?

Answer 1

balance between normal blood functioning and preventing blood loss

Question 2

where is haemostasis most effective?

Answer 2

small blood vessels (arterioles), capillaries and venules

Question 3

what is haemostasis a complex interaction between?

Answer 3

vasoconstriction
platelets
coagulation (clotting factors + inhibitors)
fibrinolysis

Question 4

name the two types of blood clotting and the substances involved in each

Answer 4

venous - clotting factors activated (inherited/acquired)

arterial - involves platelets

Question 5

what is a thrombosis?

Answer 5

formation of a thrombus within the vessel

Question 6

what can cause a thrombus?

Answer 6

pooling of blood in veins - DVT

damaged vessels - atheromatous plaques

Question 7

describe the formation of a thrombus

Answer 7

fibrin framework - platelets and other blood cells become trapped
attached to vessel wall - leads to impeded blood flow and reduced profusion of tissue

Question 8

what is the difference between a venous and arterial thrombosis?

Answer 8

venous - coagulation major factor

arterial - platelet aggregation major factor - coagulation also involved

Question 9

what is an embolus?

Answer 9

fragment or whole thrombus which detaches from wall of blood vessel

Question 10

what happens when an embolus occurs?

Answer 10

fragment or whole thrombus travels through blood vessels- blocks small vessels in pulmonary, cardiac, CNS circulation

Question 11

what results from a embolus?

Answer 11

pulmonary embolism (PE)
myocardial infarction (MI)
stroke

Question 12

what might be targeted to modify the thrombosis process?

Answer 12

• coagulation (most useful in venous thrombosis)
• platelet aggregation (important in arterial thrombosis)
• clot, thrombus breakdown (if prophylaxis fails)
  (drugs aim to inhibit thrombus without preventing haemostasis)

Question 13

what drugs are used to modify coagulation?

Answer 13

heparins (anticoagulants)

Question 14

is heparin present in the body naturally?

Answer 14

yes - present in lungs, liver and mast cells

Question 15

what impact does the molecular weight of the heparin have?

Answer 15

heparin - standard, unfractioned (natural form)
low MW heparin - more effective, less side effects
both activate anti-thrombin

Question 16

name two low MW heparins

Answer 16

enoxaparin - clexane

dalteparin

Question 17

describe the action of heparin

Answer 17

• activates anti-thrombin (AT)
• activated AT forms complexes with clotting factors: thrombin, factors Xa (+ FIXa/XIa) causing them to be inactivated
• heparin increase rate of complex formation

Question 18

what are some of the disadvantages to using heparin?

Answer 18

poorly absorbed orally - must be give IV or Sub-cut

risk of haemorrhage

Question 19

what would be done if haemorrhage occurred in a patient using heparin?

Answer 19

mild: cease admin
severe: give protamine sulphate (forms complex with heparin - inactivating)

Question 20

name a commonly used oral anticoagulant

Answer 20

warfarin

Question 21

how does warfarin work?

Answer 21

• related to structure of vit. K
• antagonises vit K role in formation of various clotting factors (II- prothrombin, VII and IX)
• warfarin prevents conversion of these active factors
• precursors to these factors are inactive in coagulation

Question 22

what are the problems associated with warfarin?

Answer 22

slow onset - fully anti-coagulated after 3 days
activity influenced by vit K - intake, absorption, gut flora
probs with antibiotics
many interactions - foods/drugs
risk of haemorrhage

Question 23

what is the INR target for recurrent DVT?

Answer 23

3.0 (2.5-3.5)

Question 24

when taking warfarin haemorrhage is at increased risk, what would you do to reverse the effect of warfarin?

Answer 24

mild: stop admin
severe: vit K, clotting factors, whole blood, fresh frozen plasma

Question 25

can warfarin be used during pregnancy?

Answer 25

no - teratogen (must be avoided in early pregnancy and ideally throughout)

Question 26

how can warfarin interact with other drugs?

Answer 26

enzyme induction - eg. carbamazepine | enzyme inhibition - eg. cimetidine

Question 27

name two of the new generation of anticoagulants

Answer 27

Rivaroxaban (Xarelto) | Dabigatran (Pradaxa)

Question 28

what is the target for Rivaroxaban?

Answer 28

inhibitor of Factor Xa

Question 29

what is the target for Dabigatran?

Answer 29

thrombin inhibitor

Question 30

what happens when platelets are activated?

Answer 30

the platelets form 'legs' which stick to other platelets

Question 31

explain the process of platelet aggregation

Answer 31

``` vessel damaged collagen exposed platelets bind here and are activated increased synthesis of TxA2 increased GPIIb/IIIa receptors expression on platelet platelets aggregate ```

Question 32

which two substances are produced from an atheromatous plaque by the COX enzyme?

Answer 32

``` thromboxane A2 (TxA2)- promotes aggregation of platelets by reducing cAMP Prostacyclin (PGI2) - reduces platelet aggregation by increasing cAMP * a balance of both is important ```

Question 33

name three targets for affecting platelet activation and aggregation

Answer 33

synthesis of thromboxane A2 cAMP levels in platelets Glycoprotein IIb/IIIa receptors on platelets

Question 34

What is the action of Aspirin as an antiplatelet drug?

Answer 34

irreversibly blocks platelet COX enzyme - reducing TxA2 synthesis (platelets won't clump together) platelets have no nuclei so no new enzyme is synthesised (eg. aggregation reduced)

Question 35

why is only a low dose of aspirin given as a antiplatelet drug?

Answer 35

``` low dose (75mg) used to avoid reducing enzyme in endothelium (PGI2) * aspirin alters balance of platelet TxA2 and endothelial PGI2 ```

Question 36

What is the action of Dipyridamole as an antiplatelet drug?

Answer 36

``` inhibits phosphodiesterase (PDE) enzyme - prevents breakdown of cAMP in platelets (eg. reduces platelet aggregation) blocks adenosine uptake into platelets, red cells and endothelial cells - inhibits TxA2 synthesis ```

Question 37

What is the action of Clopidogrel as an antiplatelet drug?

Answer 37

inhibits glycoprotein IIb/IIIa receptor expression on platelets inhibits ADP recetors - blocking activation of the glycoprotein IIb/IIIa pathway (this is the final common pathway for platelet aggregation/ important in cross linking platelets and fibrin)

Question 38

what are fibrinolytic drugs used for?

Answer 38

dissolve pre-existing clot or thrombus - most effective in acute/emergency situation (within 6hrs of onset)

Question 39

name four fibrinolytic drugs

Answer 39

alteplase reteplase urokinase streptokinase

Question 40

what are the dangers of using fibrinolytic drugs?

Answer 40

danger of haemorrhage - clotting factors used up | risk of emboli - fragment could split from thrombus

Question 41

how are fibrinolytic drugs usually administered and why?

Answer 41

IV or intracoronary admin as fast acting

Question 42

explain how alteplase works

Answer 42

inside thrombus fibrin strands bound to plasminogen alteplase binds to this complex and converst inactive plasminogen to active plasmin plasmin then digests fibrin - thrombus dissolves

Question 43

name an anti-fibrinolytic drug

Answer 43

tranexamic acid - reduces activation of plasminogen to plasmin

Question 44

when would anti-fibrinolytic drugs be used?

Answer 44

when high risk of bleeding - such as bleeding disorders