Drugs Affecting Haemostasis and Thrombosis Flashcards
What are the main constituents of coagulation?
- Vessel wall lined by endothelium
- Platelets- derived from megakaryocytes in marrow
- Coagulation factors in un-activated state
- Inhibitors of coagulation
- Fibrinolytic system and inhibitors
Describe platelet-vessel wall interaction
- Adhere to vessel wall via Von Willibrand’s factor and Glycoprotein Ib
- Adhere to each other via Glycoprotein IIb-IIIa and fibrinogen
- Granule release
- Fibrin formation
What is the coagulation cascade?
• Factors present in inactive state- activated by “intrinsic or extrinsic” pathway
What are some pathways that activate the coagulation cascade?
Tissue factor (extrinsic) pathway Contact activation (intrinsic) pathway Common pathway
What blood products can be used as drugs to help blood clot/prevent bleeding
• Blood products
- Platelets-derivedfromblooddonation
- 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
What is tranexamic acid?
- Anti-fibrinolytic drug
- Oral or IV
- Inhibits activation of plasminogen to plasmin
- Uses in trauma/GI bleeding/post op or delivery
Describe the results of the CRASH 2 trial
- 20,000 trauma patients
given bolus plus one more dose of tranexamic acid or placebo.
Effective only if given in first 3-4 hours. No increase in thrombotic events.
What vitamin is required to activate certain clotting factors?
Vitamin K
Vitamin K dependent clotting factors
What part of the vitamin K cycle is inhibited by warfarin?
Vitamin K ecocide and Vitamin K reductase
What is Warfarin?
- 1920’s- Cattle dying of haemorrhage after eating mouldy clover
- Coumarin isolated at Wisconsin Alumni Research Federation warfarin
- Inhibits production of vitamin K in reduced form
- Standard oral anticoagulant 1940’s-2010
- Effect measured by prothrombin time ( expressed as INR)- venous or capillary sample
What are the positive aspects of warfarin?
- Established for decades
- Cheap
- Easily measurable effect
- Can be reversed with vitamin K or factor concentrate
What are the 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”
What drugs increase the effect of 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
What drugs decrease the effect of warfarin?
• Rifampicin, carbamazepine, phenytoin, chronic alcohol intake- enzyme induction
What are the indications of 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 can be done to reduce stroke risk in atrial fibrillation
• Be aware of -absolute and relative risk reduction -balance of risks and benefits
-scoring risk of thrombosis (CHA2DS2-VASc) and bleeding (HAS-BLED)
What are the different aspects of CHA2DS2-VASc scoring system
Hooo boy, really rolls of the tongue eh?
Right:
C - congestive heart failure (or left ventricular systolic dysfunction)
1 point
H - Hypertension - BP consistently above 140/90 mmHg (or treated on medication)
1 point
A2 - Age =/> 75 years
2 points
D - Diabetes mellitus
1 point
S2 - Prior stroke or transient ischaemic attack or thromboembolism
2 points
V - Vascular disease
1 point
A - Age 65 - 74 years
1 point
Sc - sex category (ie female)
1 point
What is the stroke risk in % compared to CHA2DS2-VASc score?
0 - Around 1% chance 1 - 1.3% 2 - 2.2% 3 - 3.2% 4 - 4.0% 5 - 6.7% 6 - 9.8% 7 - 9.6% 8 - 12.5% 9 - 15.2%
Is warfarin effective at reducing strokes?
Between CHA2DS2-VASc 3-8 Yes absolutely
What are Direct OralAnticoagulants (DOACs)?
- Xa inhibitors eg apixaban, rivaroxaban, edoxaban
* Direct thrombin inhibitors eg dabigatran
What are the factors that favour warfarin in the warfarin vs DOACs debate?
- Established drug
- Cheap- but needs monitoring
- Can be reversed
- Effect can be easily measured
- Can be used with poor renal function
What are the factors that favour DOACs in the warfarin vs DOACs debate?
- Good trial evidence
- No monitoring needed
- Lower bleeding risk
- As effective for stroke prevention
- Reversal agents recently availablebut ££££!
- Short half life
What is heparin?
• Naturally occurring anticoagulant- discovered 1916- 2nd year student
• Can be extracted from lung and liver
• Given as IV – unfractionated- half life <1 hour
or s/c – low molecular weight (LMWH)- half life approx. 12 hours
• Binds to and activates anti-thrombin so reducing Xa and thrombin generation
What monitoring occurs in heparin administration?
• 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 weightorpregnancy. Anti-Xalevelsgivemeasureoflevelof 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 site of injection
- Increased bleeding risk
- Osteoporosis with prolonged use
- Heparin-induced thrombocytopenia- antibody mediated, 5-10 days into treatment
What drugs are used to modify platelet function?
Aspirin
Clopidogrel
Describe the use of 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
Describe the use of 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
What are 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 catheters
- Cause breakdown of fibrin and fibrinogen
- Increased bleeding risk in hours after dose
- Stenting and clot removal are alternative treatments
