Heparin
Biochemistry
Naturally occurring anticoagulant
- mixture of sulphated mucopolysaccharide chains
- heterogenous molecular weights
- average ~ 15 000 daltons
Found in granules of mast cells
- mast cells have IgE receptors on surface
- discharge when IgE-coated antigens bind to receptors
- mediate allergic reactions
Action
Facilitates action of Anti-Thrombin III
- binds to it & causes conformational change
- increased affinity for thrombin (x 1000) & Xa
- also inhibits aggregation of platelets
Pharmacology
Calcium / Sodium heparin
Half-life
- 2 hours
Reversed with Protamine
Treatment Dose
Bolus 5000 units IV
Maintenance 1000 u /hr
Maintain APTT 70-120
Levels
- check after 6 hours
- 6 hours after any change in infusion rate
- daily APTT otherwise
Prophylaxis Dose
Fixed low-dose heparin
- 5000 units s/c bd or tds
Complications
Wound haematoma
Heparin Induced Thrombocytopenias / HITS
- paradoxical thrombosis
- occurs in 10-15% of patients receiving heparin
- due to drug-antibody binding to platelets
- resolves promptly with ceasing heparin
- 80% cross-reactivity with LMWHs
LMWH (Low Molecular Weight Heparin)
Definition
Fractionated heparin
- derived from heparin by chemical / enzymatic depolymerisation
- MW 5000
Action
Pure Anti Xa
- to inactivate thrombin the chain has to attach to antithrombin III & heparin simultaneously
- because LMWH are too short to do this they only inhibit Xa
- less platelet interaction
Increased anti-thrombosis
Decreased bleeding
- because no anti-thrombin action
Pharmacology
Longer T1/2 x4
Increased bioavailability 90% vs 30%
- doesn't bind to plasma proteins as heparin does
Clexane / Enoxeparin
Derived from the intestinal mucosa of pigs
Dosing
- 0.5 mg/kg od for prophylaxis
- 1mg/kg od therapeutic dose
No monitoring required
Reduce dose
- GFR < 30
Reversal
- protamine has some, but reduced effect
Fragmin / Dalteparin
Dose
- 5000IU od
Results
Hull et al Arch Int Med 2000
- RCT of 1000 THR of warfarin v dalteparin
- warfarin had rates total DVT 24%, proximal DVT 1% and symptomatic DVT 4.5%
- dalteparin had rates total DVT 13%, proximal DVT 1% and symptomatic DVT 1.5%
- dalteparin preoperatively had slightly decreased rates of total DVT but increased bleeding
Oral Factor Xa inhibitors
Mechanism
Act directly on Factor X
- do not use ATIII as an intermediate
Advantage
Oral administration
- make OPD dosing more simple
- don't require monitoring
Interaction
Statins
Xarelto / Rivaroxaban
Dose
- 10 mg od
Results
Kakkar et al Lancet 2008
- RCT of 2500 THR patients
- 35 days of rivaroxaban v 14 days enoxeparin
- incidence DVT and non fatal PE 2% in rivaroxaban v 9% in enoxeparin (significant)
- incidence of bleeding was 6% rivaroxaban and 5% enoxeparin (non significant)
Turpie et al Lancet 2009
- RCT of 3100 TKR patients
- rivaroxaban v enoxeparin 10 - 14 days
- incidence of DCT / non fatal PE 7% rivaroxaban v 10% enozeparin (significant)
- incidence of bleeding 0.7% rivaroxaban v 0.3% enoxeparin (non significant)
Warfarin
Mechanism
Structural analogue of vitamin K
- blocks the activation of vitamin K
- factors II, VII, IX, X & Protein C + S are vitamin K dependent
Disadvantage
1. Paradoxical procoagulant effect
- initial period
- needs cover with another anticoagulant
2. Teratogenic
- contraindicated in pregnancy
3. Delayed Effect
- half-life of factors ranges between 6 and 60 hours
- FVII has the shortest half-life and is the first to be affected
- decrease of FVII increases PT
- there is a window period of 3/7 with increased PT but no true anticoagulation exists
- must cover patient for the first 3 days
4. Requires monitoring
Metabolism
Oral warfarin is readily absorbed & almost entirely albumin-bound
Metabolised in liver
Potentiators
- Cimetidine
- Phenytoin
- Trimethoprim
- Cephalosporins
- Tramadol
Inhibitors
- Rifampicin
- Phenobarbitone
Reversed with parenteral Vit K or FFP
Dosing
Starts simultaneously
- 5 mg nocte for 2 days
- then daily dose as per INR
- usually 3 - 5 mg
Treatment INR
- 1.5-2.5 DVT
- 2.5-4.0 PE
Prophylaxis INR
- 1.5 - 2
Results
Mismetti et al J Thromb Hemost 2004
- meta-analysis
- vitamin K antagonists less effective than LMWH in preventing total or proximal DVT
- no significant difference in rates of major bleeding or haematoma
Aspirin
Mechanism
- irreversibly inhibits cyclo-oxygenase in platelets & megakaryocytes
- blocks thromboxane A2 formation
Dosing
150 - 300 mg od
Disadvantages
GI bleeding
Results
PEP Trial
- RCT aspirin v placebo after 13 000 hip fractures and 4000 TKR/THR
- > 99% follow up for 35 days
IVC Filter
Indications
- complications of anticoagulation therapy
- recurrence of PE whist fully anticoagulation
- high rate of death if subsequent event / further embolic load on right ventricle
Disadvantage
Surgical procedure
- inserted through groin
- need to be removed
Results
Bicalo et al J Arthroplasty
- filter vs IV heparin
- 3 of 28 complications for heparin
- 1 of 26 for filter