Chemoprophylaxis

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