Drugs effecting haemostasis and thrombosis Flashcards
Anticoagulants
Work by inhibiting specific parts of the coagulation pathway and therefore reducing fibrin formation.
Antiplatelets
Work by inhibiting the activation and/or aggregation of platelets, therefore reducing thrombus formation.
Fibrinolytics
Used to dissolve blood clots.
Vitamin K
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
Warfarin
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.
Heparin
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)
Rivaroxaban and apixaban
orally active inhibitors of activated factor 10, no monitoring needed, caution in renal impairment, active within a few hours. Reversal agent in development.
Dabigitran-
orally active inhibitor of activated factor 2 (thrombin), no monitoring needed, caution in renal impairment, active within a few hours. Reversal agent available (expensive!)
Aspirin
Antiplatelet. Works by inhibiting cyclooxygenase (will cover this later in the module), which reduces platelet aggregation.
Clopidogrel
Antiplatelet. Acts as an antagonist for ADP receptors and prevents aggregation of platelets.
Alteplase
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.
how do platelets adhere to the wall
Adhere to vessel wall via Von Willibrand’s factor and Glycoprotein Ib
Drugs to help blood clot/prevent bleeding
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
Tranexamic acid
- Anti-fibrinolytic drug
- Oral or IV
- Inhibits activation of plasminogen to plasmin
- Uses in trauma/GI bleeding/post op or delivery
positive aspects of warfarin
- established for decades
- cheap
- easily measurable effect
- can be reversed with vitamin K or gator concentrate
negative aspects of warfarin
- 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
drugs used to increase the effector warfarin
- Amoxycillin- reduce gut vit K
- Erythromycin, statins, acute alcohol intake- enzyme inhibition
- Aspirin, clopidogrel, NSAIDs- increase bleeding risk- platelet function and GI mucosal damage
drugs used to decrease the effect of warfarin
• Rifampicin, carbamazepine, phenytoin, chronic alcohol intake- enzyme induction
Warfarin- indications
- 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
Stoke risk reduction in atrial fibrillation
- absolute and relative risk reduction
- balance of risks and benefits
- scoring risk of thrombosis (CHA2DS2-VASc) and bleeding (HAS-BLED)
Direct Oral Anticoagulants (DOACs)
- Xa inhibitors eg apixaban, rivaroxaban, edoxaban
* Direct thrombin inhibitors eg dabigatran
Favours DOACs
- 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
monitoring of heparin users
- 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)
adverse effects pf heparin
- Pain at site of injection
- Increased bleeding risk
- Osteoporosis with prolonged use
- Heparin-induced thrombocytopenia- antibody mediated, 5-10 days into treatment
Drugs to modify platelet function-aspirin
- 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
Drugs to modify platelet function- clopidogrel
• 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
Thrombolytic drugs
- 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
