Drugs Affecting Homeostasis and Thrombosis Flashcards
Which blood products can be used to help blood clot / prevent bleeding?
- Platelets - derived from blood donation
- Fresh frozen plasma - 200ml of plasma from blood donation. Contains coagulation factors in normal proportions. Dose = 15ml/Kg
- Cryoprecipitate - cooling of plasma to ~4℃ leaves behind a milky substance which contains concentrated fibrinogen, Von Willebrand factor and factors 8 and 9.
Describe the use of tranexamic acid.
- Helps blood clot and prevents bleeding.
- Anti-fibrinolytic drug
- Inhibits the activation of plasminogen to plasmin
- Oral or IV
- Used in trauma, bleeding, post operatively or post delivery.
- Clinical trial - effective only if given in first 3-4 hours. Did not cause an increase in thrombotic events.
Describe vitamin K-dependent clotting factors
What is the mechanism of action of warfarin?
Inhibits production of vitamin K in reduced form.
Compare and contrast the positive and negative aspects of warfarin use.
-
Positive aspects
- Established for decades
- Cheap
- Easily measurable effect
- Can be reversed with vitamin K or factor concentrate
-
Negative aspects
- Lots of drug interactions to enhance or inhibit its effect
- Slow onset - several days (3-6)
- Unpredictable dose need
- Needs regular blood testing
- Risk of bleeding
- Narrow ‘therapeutic window’
What are the drug interactions which increase the effect of warfarin?
- Amoxycillin - reduces absorption of gut vitamin K.
- Erythromycin, statins and acute alcohol intake - enzyme inhibition.
- Liver enzymes metabolise drugs so enzyme inhibition increase drug effect.
- Aspirin, clopidogrel, NSAIDs - increase bleeding risk; platelet function and GI mucosal damage.
What are the drug interactions which decrease the effect of warfarin?
- Rifampicin, carbamazepine, phenytoin, chronic alcohol intake - enzyme induction.
- Liver enzymes metabolise warfarin so increase in these enzymes decreases the effect of warfarin.
What are the indications for warfarin?
- 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.
What are the factors to be aware of when prescribing warfarin to atrial fibrillation patients?
- Absolute and relative risk reduction (ie 2% vs. 50%).
- Balance of risks and benefits.
- Scoring risk of thrombosis (CHA2DS2-VASc) and bleeding (HAS-BLED).
What is the mechanism of action of direct oral anticoagulants (DOACs)?
- Xa inhibitors
- Prevent the activation of factor X (which allows prothrombin → thrombin) and therefore reduces clotting.
- Apixaban
- Rivaroxaban
- Edoxaban
-
Direct thrombin inhibitors
- Dabigatran
Compare and contrast use of Warfarin and DOACs.
- Favours Warfarin
- Favours DOACs
- Established drug
- Good trial evidence
- Cheap - but needs monitoring
- No monitoring needed
- Can be reversed
- Lower bleeding risk
- Effect can be easily measured
- As effective for stroke prevention
- Can be used with poor renal function
- Reversal agent for dabigatran
- Short half life
What is the mechanism of action of heparin?
Binds to and activates anti-thrombin, reducing Xa and thrombin generation.
What is heparin?
- Naturally occurring anticoagulant (discovered 1916).
- Can be extracted from lung and liver.
- Given as IV - unfractioned - half life <1 hour. Active the minute you give it and can be reversed by protamine.
- Or subcutaneously - low molecular weight - half life ~12 hours.
How is heparin monitored?
- IV heparin is monitored by APPT plasma testing and dose is adjusted.
-
Subcutaneous low molecular weight heparin (LMWH) such as 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 level give measure of level of anticoagulation.
- Both used for treatment and prevention of DVT / PE.
- All patients on admission assessed for thromboembolism risk (VTE).
What are the adverse effects of heparin?
- Pain at the site of injection
- Increased bleeding risk
- Osteoporosis with prolonged use
- Heparin-induced thrombocytopaenia - antibody mediated, 5-10 days into treatment (antobodies latch onto platelets and cause significant drop in platelets)
Describe the mechanism of action of aspirin as an anti-platelet.
Low doses (75-150mg/day) can cause irreversible inhibition of COX-1; causing less thromboxane A2 production and therefore less aggregation of platelets.
When is aspirin indicated as an anti-platelet?
- Typically used after TIA or MI.
- Some effect in stroke prevention in AF but not as effective as warfarin / DOAC.
What are the risks of using aspirin as an anti-platelet?
- Increased GI bleeding risk
- Dyspepsia
What is the anti-platelet mechanism of action of clopidogrel?
Inhibits ADP-induced platelet aggregation
How is clopidogrel used as an anti-platelet?
- Used with aspirin to prevent recurrent MI
- Used in ischaemic stroke and TIAs
- Increased risk of dyspepsia and GI bleeding
Describe the duration of action of aspirin and clopidogrel.
There are no reversal agents for aspirin and clopidogrel, so the effect will last the duration of platelet lifespan (~5-10 days).
Describe the action of thrombolytic drugs.
- Drugs to increase the activation of plasminogen to plasmin.
- Tissue plasminogen activators (tPA) e.g. streptokinase and alteplase, are used for thrombolysis of the brain/heart/occluded venous catheters.
- They cause breakdown of fibrin and fibrinogen.
What is the main risk associated with using thrombolytic drugs?
Increased bleeding risk in the hours after the dose.
What are the alternative treatments to thrombolytic drugs?
- Stenting
- Clot removal
