Drugs effecting haemostasis and thrombosis

Question 1

Anticoagulants

Answer 1

Work by inhibiting specific parts of the coagulation pathway and therefore reducing fibrin formation.

Question 2

Antiplatelets

Answer 2

Work by inhibiting the activation and/or aggregation of platelets, therefore reducing thrombus formation.

Question 3

Fibrinolytics

Answer 3

Used to dissolve blood clots.

Question 4

Vitamin K

Answer 4

Required as a co-factor in the production of factors 2, 7, 9, 10, and can be used to reverse effects of warfarin but takes 6-12 hours to work

Question 5

Warfarin

Answer 5

Oral anticoagulant which inhibits production of active (reduced) vitamin K and hence factors 2, 7, 9, 10. Requires monitoring with International Normalised Ratio (INR), an adjusted prothrombin time. It takes 2-5 days to achieve therapeutic anticoagulation.

Question 6

Heparin

Answer 6

Intravenous (unfractionated) or subcutaneous (low molecular weight) anticoagulant.
Faster working than warfarin (acts almost immediately). Binds to and activates anti-thrombin (naturally occurring inhibitor of coagulation) and thus inhibits formation of activated factors 10 (Xa) and 2 (IIa)

Question 7

Rivaroxaban and apixaban

Answer 7

orally active inhibitors of activated factor 10, no monitoring needed, caution in renal impairment, active within a few hours. Reversal agent in development.

Question 8

Dabigitran-

Answer 8

orally active inhibitor of activated factor 2 (thrombin), no monitoring needed, caution in renal impairment, active within a few hours. Reversal agent available (expensive!)

Question 9

Aspirin

Answer 9

Antiplatelet. Works by inhibiting cyclooxygenase (will cover this later in the module), which reduces platelet aggregation.

Question 10

Clopidogrel

Answer 10

Antiplatelet. Acts as an antagonist for ADP receptors and prevents aggregation of platelets.

Question 11

Alteplase

Answer 11

Fibrinolytic. Is an enzymatic Tissue Plasminogen Activator. Binds to fibrin (preferentially to that within a clot), activates plasminogen which releases plasmin. Plasmin the breaks down fibrin and dissolves the clot.

Question 12

how do platelets adhere to the wall

Answer 12

Adhere to vessel wall via Von Willibrand’s factor and Glycoprotein Ib

Question 13

Drugs to help blood clot/prevent bleeding

Answer 13

Blood products:

• Platelets- derived from blood donation
• Fresh frozen plasma- 200ml plasma from blood donation- contains coag factors in normal proportions. Dose 15 ml/Kg
• Cryoprecipitate- pools of 5 donations using precipitate at 4C- concentrated fibrinogen, Von Willebrand factor and VIII
• Specific coag factors eg IX VIII fibrinogen

Question 14

Tranexamic acid

Answer 14

• Anti-fibrinolytic drug
• Oral or IV
• Inhibits activation of plasminogen to plasmin
• Uses in trauma/GI bleeding/post op or delivery

Question 15

positive aspects of warfarin

Answer 15

• established for decades
• cheap
• easily measurable effect
• can be reversed with vitamin K or gator concentrate

Question 16

negative aspects of warfarin

Answer 16

• lots of drug interactions to enhance or inhibit effect
• slow onset (several days)
• unpredictable dose need
• needs regular blood testing
• risk of bleeding
• narrow therapeutic window

Question 17

drugs used to increase the effector warfarin

Answer 17

• Amoxycillin- reduce gut vit K
• Erythromycin, statins, acute alcohol intake- enzyme inhibition
• Aspirin, clopidogrel, NSAIDs- increase bleeding risk- platelet function and GI mucosal damage

Question 18

drugs used to decrease the effect of warfarin

Answer 18

• Rifampicin, carbamazepine, phenytoin, chronic alcohol intake- enzyme induction

Question 19

Warfarin- indications

Answer 19

• Deep vein thrombosis (DVT) and pulmonary embolism (PE)- short or long term depending on whether recurrent and/or provoked
• Prosthetic heart valve replacement
• Atrial fibrillation to reduce stroke risk

Question 20

Stoke risk reduction in atrial fibrillation

Answer 20

• absolute and relative risk reduction
• balance of risks and benefits
• scoring risk of thrombosis (CHA2DS2-VASc) and bleeding (HAS-BLED)

Question 21

Direct Oral Anticoagulants (DOACs)

Answer 21

• Xa inhibitors eg apixaban, rivaroxaban, edoxaban

* Direct thrombin inhibitors eg dabigatran

Question 22

Favours DOACs

Answer 22

• Good trial evidence
• no monitoring needed
• lower bleeding risk
• as effective for stroke prevention
• reversal agents recently available but cost a lot
• short half life

Question 23

monitoring of heparin users

Answer 23

• IV heparin is monitored by APPT plasma testing and dose adjusted
  • S/c LMWH eg dalteparin
• used as fixed dose for prophylaxis and weight adjusted dose for treatment
• no routine monitoring unless poor renal function, extreme body weight or pregnancy. Anti-Xa levels give measure of level of anticoagulation
  -Both used for treatment and prevention of DVT/PE
  -All patients on admission assessed for thromboembolism risk (VTE)

Question 24

adverse effects pf heparin

Answer 24

• Pain at site of injection
• Increased bleeding risk
• Osteoporosis with prolonged use
• Heparin-induced thrombocytopenia- antibody mediated, 5-10 days into treatment

Question 25

Drugs to modify platelet function-aspirin

Answer 25

• Aspirin- low doses eg 75-150mg/day cause irreversible inhibition COX-1 so less thromboxane A2 production- less aggregation of platelets
• Typically used after transient ischaemic attack (TIA) or myocardial infarction
• Some effect in stroke prevention in AF but not as effective as warfarin/DOAC
• Increase in GI bleeding risk, dyspepsia

Question 26

Drugs to modify platelet function- clopidogrel

Answer 26

• Inhibit ADP induced platelet aggregation
• Used with aspirin to prevent recurrent myocardial infarction • Used in ischaemic stroke and TIAs
• Increased risk of dyspepsia and GI bleeding
No reversal agents for aspirin and clopidogrel so effect will last the duration of platelet lifespan- 5-10 days

Question 27

Thrombolytic drugs

Answer 27

• Drugs to increase activation of plasminogen to plasmin
• Tissue plasminogen activators (tPA) eg streptokinase and alteplase- used for thrombolysis brain/heart/occluded venous cathethers
• Cause breakdown of fibrin and fibrinogen
• Increased bleeding risk in hours after dose
• Stenting and clot removal are alternative treatments