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§        Naturally occurring glycosaminoglycan extracted from porcine mucosa (15,000 Da)

§        Anticoagulant properties depend on the presence of a specific pentasaccharide sequence which binds with high affinity to antithrombin and potentiates its activity

§        LMW heparin manufactured from heparin (3-5000 Da)


§        Anti-Xa activity requires only the activity of the pentasaccharide sequence (1700Da), but anti-IIa activity (thrombin inhibition) requires minimum chain length of 18 saccharides

§        Thus, in all LMWH anti-Xa activity >  anti-IIa activity


§        Dosage of LMWHs correlates better with anti-Xa activity, however both effects probably contribute to anticoagulant effect

§        Fondaprinux, synthetic pentasaccharide is efficacious also and has no anti-IIa activity

§        Precise mechanism of LMW heparin not understood and may not depend on Xa or IIa activity eg release of TFPI



§        Metabolism is by a saturatable mechanism

§        Binding to endothelial cells and clearance by reticuloendothelial system

§        Non-saturable mechanism

§        Renal clearance (predominates for LMWH)

§        No evidence that they cross the placenta

§        Pharmacokinetics

§        Half ife

§        LMWH iv – 2 hours

§        UFH iv – 1 hour

§        LMWH sc – 4 hours

§        Bioavailability

§        LMWH sc – 90-100%

§        UFH sc - <50%

§        Antagonists

§        Platelet factor 4 and protamine

§        Reduced binding affinity with reduced molecular weight

§        LMWH require higher doses for neutralisation

§        All LMWHs have a proportion of factor Xa activity which is non-neutralisable (<18 saccharides)

§        Animal studies suggest that this does not affect the ability of protamine to reverse bleeding


Prophylactic heparin

§        General and gynae surgery

§        LMWH or UFH at prophylactic dose

§        LMWH probably preferable due to reduced incidence of HIT

§        Major elective orthopaedic surgery

§        Original papers showed prophylactic heparin reduced DVT / PE / Fatal PE all by 2/3 and total mortality by 21% (Collins et al 1988 metaanalysis in NEJM)

§        LMWH or fondaparinux at prophylactic dose for at least 7-10 days

§        Consider extended prophylaxis in high risk patients (usually up to 5 weeks)

§        Fondaparinux

§        Possibly more effective than LMWH (12 v 27% DVT post knee surgery – NEJM 2001) but excess major bleeding in the fondaparinux arm

§        Doesn’t appear to x-react with anti-PF4/ heparin antibodies

§        Aspirin PEP trial (2000) showed 1/3 reduction in DVT and PE compared to placebo

§        No comparison with heparin – not currently recommended in BSH or ASH guidelines

§        Hip fracture

§        LMWH or fondaparinux at prophylactic dose

§        Again fondaparinux possibly better (9% v 17%) NEJM 2001

§        Major trauma

§        As above if not contraindicated by bleeding risk

§        Lower limb plaster casts

§        LMWH reduces asymptomatic DVT but not fatal PE

§        Prophylaxis can be considered in high risk patients

§        Neurosurgery

§        Mechanical methods of thromboprophylaxis may be preferred

§        Medical patients

§        Those deemed at high risk (age >60, cardiac / respiratory failure, infection / inflammation) should have prophylaxis 10% risk reduced to 5%

§        Cancer             

§        Small studies showing survival advantage in patients without DVT / PE

§        Routine primary prophylaxis not recommended

§        Not recommended for use as an anti-neoplastic agent outside clinical trial

§        Sickle cell

§        No evidence that reduces severity of crisis

§        Should be considered for prophylaxis

§        Pregnancy and the puerperium

§        Due to altered pharmacokinetics

§        Twice daily dosing

§        Anti-Xa activity should be measured to ensure appropriate dosing for therapeutic doses

§        Monitor plt count

§        If VTE early in pregnancy, can go to prophylactic dose after 6 months

§        Advise not to administer further injections once labour started

§        Heparin associated skin necrosis more common during pregnancy



Venous thromboembolism


§        LMW heparin recommended

§        DVTs can be treated at home (also possible for PE)

§        IV heparin dosing

§        5000units (75u/kg) bolus followed by 18u/kg/hr

§        APTT 4 hours after a dose change


Cerebral venous sinus thrombosis

§        Evidence is for UFH

§        ICH is not a contraindication to treatment


Intraabdominal thrombosis

§        Portal vein, mesenteric vein, renal vein

§        Little evidence – UFH/LMW heparin followed by warfarin


Superficial vein thrombosis

§        Most cases are self limiting

§        Some have concurrent DVT

§        Most likely with proximal involvement of long saphenous vein

§        Very few studies, have concluded that prophylactic ir therapeutic doses of LMWH may reduce progression/ recurrence of superficial thrombophlebitis but not sufficient data to demonstrate a reduction in DVTs



§        CLOT study

§        Acute DVT / PE in patients with cancer randomised to dalteparin or coumarin INR 2.5 (secondary prophylaxis) with LMWH resulted in 9% recurrence compared to 17% with oral anticoagulation


Arterial thromboembolism

Myocardial Infarction

§        LMWH should be considered for all patients with acute MI

§        Patients at hight risk of systemic or pulmonary emboli should be considered for initial treatment with iv UFH

§        Anterior Q wave infarctions

§        Severe LV dysfunction

§        Congestive cardiac failure

§        History of embolism

§        Mural thrombus

§        AF

§        Patients receiving thrombolytic therapy should be considered for 48 hours of iv UFH


§   Acute Coronary Syndromes

§        LMWH or UFH in addition to aspirin (original trials of heparin in addition to aspirin showed 33% reduction in MI and death – Oler et al 1996)

§        Coronary angioplasty

§        Iv heparin before, during and for 24 hours after

§        Not routine to continue iv heparin following CABG



§        Benefit offset by risk of haemorrhage

§        Consider prophylactic doses only


Perpipheral Vascular Reconstructive Surgery

§        Little evidence

§        Should be given at therapeutic doses


Special Situations

§        Central venous/ arterial catheters

§        Common complication of femoral lines

§        Prophylactic dose after insertion or heparin flush

§        Haemodialysis

§        Heparin used to prevent extracorporeal coagulation

§        Prostacyclin is an alternative

§        DIC – not generally used

§        Heparin may be considered in

§        Retained dead fetus syndrome

§        Giant haemangioma

§        Solid tumour

§        APML (ATRA has largely obviated the need)

§        UFH preferred because of risk of bleeding

§        Lower doses are often used



§        Relative

§        Untreated haemophilia

§        Platelets <80

§        HITT

§        Peptic ulcer

§        Recent cerebral haemorrhage

§        Severe hypertension

§        Severe liver disease

§        Oesophageal varices

§        Major trauma

§        Recent neurosurgery

§        Eye surgery

§        Spinal/ epidural anaesthesia

§        LMWH

§        CrCL <30ml/min

§        UFH preferred

§        Anti-Xa monitoring

§        Osteoporosis

§        Symptomatic vertebral fractures 2-3% receiving treatment dose UFH for > 1 month

§        Decreased osteoblasts, with reduced amounts of unmineralised collagen lining the bone surface

§        Increases osteoclast activity

§        Only slowly reversible because heparin binds to bone matrix proteins

§        LMWHs associated with a lower risk than UFH



§        1mg of protamine neutralises 80-100U of UFH when administered within 15 minutes of heparin dose

§        Less is required if administered before that, because of short half life

§        Incomplete reversal effect on LMWH

§        No neutralising effect on fondaparinux

§        Plasma infusion is ineffective

§        rVIIa has been shown to reverse LMWH in life threatening bleeding

§        rVIIa has reversed fondaparinux effect in healthy volunteers



§        UFH

§        Target APTT of 1.5 – 2.5 = Xa 0.35 – 0.7 = 0.2-0.4 U/ml

§        LMWH

§        Anti-Xa assay

§        Give no information on the anti-IIa activity

§        Different LMWHs may not be comparable at the same plasma anti-Xa concentration due to differences in IIa activity

§        Mechanism of action of LMW heparin not entirely due to IIa or Xa inhibition (eg TFPI release)

§        Requires careful assay validation – poor comparability between Xa assays

§        Gives an incomplete picture

§        Poorly predictive of antithrombotic efficacy and haemorrhage risk

§        Samples

§        4-6 hours after sc administration are suitable for assessment of peak anti-Xa levels

§        Trough level at 24 hours if accumulation suspected,

§        Not routinely indicated, but may be useful in

§        Renal impairment

§        Obese

§        Pregnant

§        Neonates/ infants





§        Synthetic selective Xa inhibitor 1728Da

§        Induces a conformational change in antithrombin that increases its affinity for Xa 300 fold

§        Only binds Xa unlike heparin and LMWH

§        Once antithrombin binds Xa fondaparinux is released and catalyse further reactions

§        Xa binds antithrombin covalently and the complex is then cleared from the circulation

§        Half life 17 hours

§        Renal excretion – contraindicated if GFR <30



§        Hip replacement 2.5mg v enoxaparin 40mg (two trials EPHESUS and PENTATHALON 2000) fondaparinux superior – 25-50% reduction in VTE rate

§        Fracuture of upper femur prophylaxis (2.5mg) v enoxaparin 40mg 8 v 19 % VTE (PENTHIFRA)

§        Knee replacement 2.5mg v enoxaparin 40mg 12 v 27 % VTE

§        11 major bleeding events (fondaparinux) v 1 for enoxaparin – no deaths

§        No difference in major bleeding in the other trials

§        No difference in fatal or non fatal PE in the metaanalysis of the trials (7500 patients)



§        Higher dose 7.5mg for 50-100kg

§        As effective as full dose LMWH or UFH


§        Acute coronary syndrome (OASIS 5)

§        Fondaparinux 2.5mg (ie prophylactic dose) was as effective as enoxaparin bd 1mg/kg

§        50% reduction in bleeding

§        Reduced mortality 2.5 v 3.5%



§        Idraparinux is a hypermethylated analogue of fondaparinux which binds antithrombin with very high affinity and has a half life of 80 hours

§        No antidote but a biotinylated form of the enzyme which has an antidote is currently in trials

§        NEJM 2007

§        Weekly idraparinux as good as heparin for DVT but less effective for PEs

§        Continued idraparinux for 6 months after standard treatment resulted in lower VTE (1 v 4%) but 11 major bleeds including 3 fatal intracranial haemorrhages


Oral direct thombin inhibitors


§   Small molecule that directly inhibits Xa

§   Currently undergoing trials