Anticoagulants & Antiplatelets Flashcards
Outline the components of Virchow’s triad.
Hypercoaguability
- genetic e.g. protein C & S deficiency, factor V deficiency
- acquired e.g. antiphospholipid synthesis, OCP, smoking, malignancy, prosthetic heart valves
Endothelial damage (arterial)
- atheroma (MI, stroke)
- hypertension
- toxins (cigarettes, homocysteine)
Stasis
- ARTERIAL (cardiac abnormality) = AF, mitral valve disease, post-MI, carotid-cavernous fistula (CCF)
- VENOUS (immobility) = ill health, post-op, economy class
Outline the clotting cascade.
Intrinsic pathway (exposed collagen, kallikrein): XII ---> XIIa XIIa catalyses XI ---> XIa XIa catalyses IX ---> IXa IXa catalyses X ---> Xa
Extrinsic pathway (tissue damage releasing tissue factor, thromboplastin, calcium): VII catalyses X ---> Xa
Xa catalyses prothrombin (II) —> thrombin (IIa)
Thrombin (IIa) cleaves fibrinogen to fibrin
XIII helps fibrin form clot
Fibrinogen & thrombin stimulate further aggregation of platelets
What inhibits the different part of the clotting cascade?
Heparin-antithrombin complex inhibits XIIa, XIa, IXa, Xa, thrombin (IIa)
Hirudin inhibits thrombin (IIa)
Warfarin inhibits production of vitamin K dependent clotting factors = IX, VII, X, prothrombin (II)
What are the functions of warfarin?
Coumarins
Inhibits production of vitamin K dependent clotting factors in liver (competitive; synthesis of non-functional clotting factors)
- stops conversion of vitamin K to active reduced form
- affects prothrombin (II), IX, X, and VII (EXTRINSIC PATHWAY)
- initially increases coagulability due to inhibition of synthesis of proteins C & S (therefore initially give heparin)
Describe the pharmacokinetics of of warfarin.
Slow onset - days (need to deplete activated clotting factors; therefore give heparin to cover)
Slow offset: t1/2 = ~48hrs (time needed to synthesise new clotting factors; need to stop 3 days before surgery)
Good GI absorption - give PO (indicated for long-term anticoagulation)
Heavily bound to albumin (caution needed with NSAIDs - displace drugs from albumin)
Metabolised by CYP450 (take caution in liver disease and with CYP450 inducers and inhibitors)
Crosses placenta - contraindicated in first trimester (teratogenic) and third trimester (risk of baby’s head bleeding as its head is distorted during vaginal delivery)
How is warfarin monitored? Why is this important?
- concentration of extrinsic pathway factors
- prothrombin time
- International Normalised Ratio (INR) = standard value; the higher the INR, the thinner the blood
Extreme variation in individual dose requirements; avoid complications of hypercoaguable blood and excessive bleeding
Give some examples of drugs potentiating the action of warfarin.
CYP450 inhibitors e.g.
- amiodarone
- quinodone
- metronidazole
- cimetidine
- alcohol (acute)
- aspirin (anti-platelet)
- reduced vitamin K secretion from gut bacteria e.g. cephalosporins
- NSAIDs displace warfarin from albumin —> increased conc. of free warfarin (temporary)
- drugs reducing GI absorption of vitamin K (temporary)
Give some examples of drugs inhibiting the action of warfarin.
CYP450 inducers e.g.
- anti-epileptics
- rifampicin
- St. John’s Wort
- chronic alcohol
What are the indications for warfarin? What are the different INR ranges for each indication?
DVT: 3-6 months (provoked for 3 months, unprovoked for 6 months), INR 2.0-3.0
PE: 3-6 months (provoked for 3 months, unprovoked for 6 months), INR 2.0-3.0
AF: until risk of bleeding exceeds benefit of reduced risk of CVS events
Mechanical prosthetic valves: INR 2.5-4.5
Recurrent thromboses on warfarin: INR 2.5-4.5
Thrombosis associated with inherited thrombophilic conditions: INR 2.5-4.5
Cardiomyopathy
MI
Stroke
What are some ADRs associated with warfarin?
Bleeding/bruising
- GI bleeding
- intracranial haemorrhage
- epistaxis
- injection site
Teratogenesis (advise in young, female patients)
Inform when to consult a doctor
Give anticoagulant card
How can warfarin be reversed?
Parenteral vitamin K (slow)
Fresh frozen blood (fast)
Prothrombin complex concentrate (fast)
Replace with heparin cover for 6 weeks
note: severe bleeding = stop warfarin and restart when INR is less than 5.0
What is heparin? What is its function? Outline its pharmacokinetics.
Pentasaccharide glycosaminoglycan with sulfate groups (-ve charge)
Produced by mast cells
Activates anti-thrombin III —> inhibits thrombin and Xa (+ IXa, XIa, XIIa)
Rapid onset and offset
Poor GI absorption (therefore give parenterally)
What is unfractionated hepatin?
~20kDa (mix of variable length chains)
Bolus then IV infusion (occasionally SC as prophylaxis - monitoring required via activated partial thromboplastin time)
Large enough to bind simultaneously to thrombin (IIa) and anti-thrombin III (catalyses inhibition of Xa)
Binds to cells and proteins (low bio-availability and unpredictable dose response)
What is low molecular weight heparin?
4-5kDa
Activates anti-thrombin III —> inhibits Xa
Too small to bind to thrombin (IIa) and anti-thrombin III (cannot catalyse inhibition of thrombin)
Given SC once or twice daily (NOT IM - causes muscular bleeding)
Higher bioavailability (90%+) than unfractionated heparin
Longer biological half life than unfractionated heparin
More predictable dose response than unfractionated heparin (does not bind to macrophages, endothelial cells, or plasma proteins)
Renal clearance
Less likely to cause thrombocytopenia
Usually no monitoring required
Give some examples of newer anti-coagulants apart from heparin and warfarin.
Selective factor Xa inhibitors e.g. fondaparinux
Direct thrombin inhibitors e.g. dabigatran
What are the indications for heparin?
Peri-operative thrombo-embolism prophylaxis (low dose of low molecular weight heparin)
Thrombo-embolism prophylaxis during immobility e.g. frail/unwell patient
Cover risk of thrombosis when warfarin is stopped e.g. surgery
Administered prior to warfarin in DVT, PE, AF (whilst warfarin loading is achieved; low molecular weight heparin used unless fine control is required)
Following acute coronary syndromes to reduce recurrence/extension of coronary artery thrombosis
Used instead of warfarin pregnancy (with caution)
Give some examples of ADRs associated with heparin.
Bruising/bleeding
- GI loss
- intracranial haemorrhage
- epistaxis
- injection site
Heparin-induced thrombocytopenia (HIT)
- 1-2 weeks following treatment
- autoimmune: immune complexes activate more platelets (and cross-link heparin and PF4) —> release of PF4 —> increased IgG deposition —> platelet deposition and thrombosis in minor blood vessels —> purpura
- indicated by widespread purpura and 50%+ reduction in platelets
- diagnose by assaying antibodies
- treatment: stop heparin and add hirudin (anti-thrombin)
Osteoporosis (rare; chronic use)
How can heparin be reversed?
Protamine sulfate = dissociates heparin from anti-thrombin III irreversibly
Given if actively bleeding (otherwise heparin is stopped and APTT is monitored if unfractionated)
- risk of anaphylaxis
- need to carefully calculate so as not to overdo anti-coagulation
Give some examples of anti-platelets.
Aspirin: irreversibly inhibits COX-1 —> reduced production of thromboxane A2 —> reduced platelet aggregation/vasoconstriction
Phosphodiesterase inhibitors: reduced PDE —> increased c.AMP activation —> reduced platelet aggregation
e.g. dipyridamole (+ve ionotrope and vasodilator used with aspirin to prevent strokes and in imaging)
ADP antagonists: ADP stimulates platelet aggregation
e.g. clopidogrel (used with aspirin to reduce risk of stent thrombosing, in acute coronary syndromes and PCI)
Glycoprotein IIb/IIIa inhibitors: inhibit fibrinogen receptor —> reduced platelet cross-linking
Abciximab: monoclonal antibody (stays in circulation for a long time)
Peptides e.g. eptifibatide, timfiban (shorter half-lives)
When are anti-platelets indicated? What is the reason for this?
High risk acute coronary syndromes
Post-PCI (percutaneous coronary intervention)
Increases risk of bleeding but reduces risk of acute thrombosis and re-stenosis
Outline thrombolysis. Give some examples of naturally occurring plasminogen activators.
Plasminogen (bound to fibrin) is activated to plasmin
Plasmin cleaves fibrin, II, V, & VIII
Plasminogen activators:
- tissue plasminogen activator (tPA)
- urokinase-type plasminogen activator (uPA)
Give some examples of fibrinolytic drugs. How do they work?
Generate plasmin e.g. alteplase (recombinant tPA)
- works preferentially in presence of fibrin (“clot-specific”)
Activate plasminogen e.g. streptokinase
- causes degree of fibrinolysis throughout circulation
- transient hypotension during infusion (slow infusion)
- bacterial product (antigenic; cannot be used twice as antibodies are generated, reducing its efficacy; risk of anaphylaxis)
When are thrombolytics indicated?
Acute MI (within 12hrs with ECG evidence)
PE
Major venous thrombosis
Clearance of thrombosed shunts and intraocular thromboses
note: benefit of treatment declines continuously over time but risk of treatment remain constant (therefore give ASAP before consequences of occlusion become irreversible)
Give some examples of ADRs associated with thrombolytics.
Haemorrhagic stroke (0.1%-0.5%)
- may require blood transfusion/volume expander infusion, specific/recombinant clotting factors or tranexamic acid or aprotinin to inhibit further fibrinolysis
- CT/MRI head in strokes to establish whether it is haemorrhagic (due to treatment) or ischaemic
GI bleeding (major in 0.5%-1%)
- N&V
- bleeding at site of injection
- in MI: reperfusion arrhythmias, recurrent ischaemia, angina
- hypotension
- allergy/anaphylaxis
When are thrombolytics contra-indicated?
Active peptic ulcer (+ other potential bleeding sites)
Recent trauma/surgery
History of stroke of uncertain aetiology, cerebral haemorrhage, uncontrolled hypertension, coagulation defects
Streptokinase given in past (cannot be given again)
note: age is not a contraindication per se
Contrast arterial and venous thromboses.
Arterial thrombosis (white clot - platelets)
- stroke (cerebrovascular accident)
- MI
- anti-platelets & thrombolysis
Venous thrombosis (red clot)
- DVT
- PE
- anti-coagulation
What is the initial management of pulmonary embolism?
- low molecular weight heparin OR fondaparinux for 5 days or until INR = 2+ for 24hrs
- warfarin for 3 months (then reassess)
- O2 to manage breathlessness (check O2 saturation)
- analgesia
- echocardiogram (?right heart greatly affected)
- CXR (look for visible pulmonary wedge - uncommon)
- ?thrombolysis
- ECG (S wave in lead I, prominent Q waves characteristic of PE)
note: D-dimers only used when deciding whether to do a CT pulmonary angiogram (CTPA)
