heparin

see:

• anticoagulants,
• Historical perspective of anticoagulants
• pharmacology main index
• warfarin
• enoxaparin
• RCH guidelines - anticoagulation therapy in children

• prior to commencement take bloods for APTT, INR, FBE, LFT's

• eg. as adjunct to thrombolysis, the elderly, anti-platelet medications, post-op.
• target APTT reduced to 50-75secs
• 5000IU (4000U if < 67kg) stat then 12-15units/kg/hr
• 25000IU in 500ml NS (=50U/ml):
  • if > 100kg, then 26ml/hr,
  • if 80kg, then 20ml/hr,
  • if 60kg, then 16ml/hr
  • NB. Metalyse (tenectaplase), product information recommends:
    • heparin 5000U IV stat (4000U if < 67kg) then 
    • infusion 25000U in 500ml NS @ 16ml/hr (<67kg) or 20ml/hr (>67kg)

• target APTT with full heparinisation is usually 60-80secs
• 80U/kg to max. 8000U stat 
• larger clot burdens may require higher doses
• raised initial APTT may require lower bolus or none
• 25000IU in 500ml NS (=50U/ml) at 20U/kg/hour (to max. 2,000U/hr) initially then titrate according to APTT.
• if maintenance dose > 35,000U/24h then check anti-Xa levels:
• if anti-Xa levels are 0.5-0.8IU/ml then indicates therapeutic levels & heparin dose should NOT be increased.
• if in doubt, consult haematology 
• check platelets 3x/week
• commence warfarin Rx within 72hrs of heparin commencement unless otherwise contraindicated
• cease when warfarin Rx has been commenced AND INR > 2.5 (or within therapeutic range) for 2 consecutive days, ie. heparin must usually be continued for at least 4 days from onset of warfarin Rx

• patients who are on full dose heparin and who need invasive procedures need to have heparin with-held:
  • for surgery, usually cease 6 hrs prior and restart 12hrs after if no evidence of bleeding
  • for procedures, may be possible to cease only 2-4hrs prior and re-start 2-6hrs after procedure if no bleeding
  • if on warfarin, warfarin can usually be re-started same night of surgery or procedure.

• 5000IU s/c 8h
• start 1-2 h prior to surgery
• NB. LMW heparin preferred in hip/knee replacement surgery when they are usually given on the night before surgery to minimise bleeding risk.

• pts whose APTT levels are subtherapeutic in 1st 24hrs may have DVT recurrence rates 15x higher than pts with Rx levels. (2nd 24hrs of Rx not as important)
• some suggest starting infusion rates at least 30000IU/day

• this is arbitarily defined as those pts requiring > 40,000 IU/day to maintain Rx level
• these pts have increased levels of factor VIII & heparin-binding proteins
• this often occurs in pts with inflammatory diseases
• elevated factor VIII levels cause dissociation b/n APTT & heparin values causing “subtherapeutic” APTT values when in fact heparin values are therapeutic.
• solutions:
  • monitor with anti-factor Xa chromogenic assay instead of APTT, or,
  • use LMW heparins instead (bind less to heparin-binding proteins)

• approx. 5% of pts Rx with IV or SC heparin have major bleeding, although excessive prolongation of APTT probably increases the risk, clinical characteristics such as recent surgery, liver disease, severe thrombocytopenia & concomitant platelet Rx are stronger predictors.
• risk is higher than for LMW heparins
• risk correlates with presence & degree of excessive prolongation of prothrombin time as indicated by higher INR caused by warfarin.

• Mx should be individualised, with Rx depending on location & severity of bleeding, lab. test results, & risk of ceasing anticoagulant Rx
• cease anticoagulant Rx
• local measures to stop bleeding
• if APTT prolonged and potentially life-threatening bleeding then give protamine
• consider insertion of caval filter in pts with recent venous thromboembolism
• see also bleeding on oral anticoagulants and patient risk stratification for thrombosis after reversal of anticoagulation

• see also platelet factor 4 antibody thrombotic and thrombocytopenia syndromes
• approx. 3% of pts on heparin Rx have immune IgG-mediated thrombocytopenia which is frequently complicated by paradoxical extension of pre-existing venous thromboembolism or new arterial thrombosis!!
• suspect if platelet count falls < 100,000 per cu.mm or < 50% of baseline value 5-15 days after Rx is begun, or sooner in a pt who received heparin in the recent past
• minimise risk of occurrence by:
  • initiating warfarin Rx early to reduce exposure to heparin
  • use LMW heparins instead
• management options (after ceasing heparin):
  • warfarin Rx:
    • problem in that it is slow-acting & can cause early transient hypercoagulability
  • caval filter:
    • prevent embolisation of pre-existing thrombi, but do not prevent extension up to the filter, thrombosis above it, or arterial thrombosis
  • rapid-acting anticoagulants:
    • danaparoid sodium - may cross-react with heparin in < 5% pts
    • BUT NOT LMW heparins - may cross-react with heparin commonly so should be avoided in this condition
    • defibrinogenating snake venom ancrod (Arvin)
    • hirudin

• occurs in ~30% with Rx duration > 1 month (eg. in pregnancy where warfarin C/I)
• risk may be lower with LMW heparins