Heparin
§ 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
Pharmacology § 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
Treatment Venous thromboembolism DVT / PE § 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
Cancer § 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
Stroke § 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
Contraindications § 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
Bleeding § 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
Monitoring § 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
Trials § 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)
§ DVT / PE (MATISSE-DVT / MATISSE-PE) § 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 § 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 Rivroxaban § Small molecule that directly inhibits Xa § Currently undergoing trials
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