thrombolytics

see also:

• pharmacology main index
• cardiology
• thrombolysis
• thrombolysis in AMI
• thrombolysis in PE
• thrombolysis in stroke
• intra-arterial thrombolysis
• Heart.org thrombolytics (pdf)
• LITFL

• also called fibrinolysis or fibrinolytics

• acts on the inactive proenzyme plasminogen to produce the active enzyme plasmin
• 1st used to lyse coronary clots: IV in 1958 & intracoronary in 1976
• 1st demonstrated to recanalise an acutely occluded coronary artery in a living pt in early 1980's
• usage in AMI:
  • aspirin x1, chewed;
  • no heparin as no added benefit with SK and only increases bleeding risk
  • 2 x IV cannulae;
  • 1.5million IU in 100ml NS over 1hr (CVS guidelines state 20-30min!)
  • if BP falls below 80mmHg:
    • place in Trendelenberg
    • consider IV fluid bolus
    • reduce infusion rate to half
  • if BP falls below 70mmHg:
    • cease infusion & recommence at half previous rate when BP > 70mmHg
• Contraindications to SK in addition to usual C/I to thrombolytics:
  • SK has been administered within 3 years unless in past 3-5 days
  • PH HS reaction to SK
  • recent streptococcal infection
• Adverse effects:
  • bleeding:
    • haemorrhagic stroke
  • hypotension (12%)
  • allergic reactions
  • anaphylaxis (rare)

• anisoylated plasminogen SK activator complex
• clinical use 1st reported in 1984
• a 2nd generation complex of SK, its active agent & acylated human lysplasminogen
• rapid acting with prolonged half life ⇒ only bolus needed ⇒ 4-6hrs of activity
• dose: 30U IV over 5min

• see alteplase

• the 1st 3rd generation thrombolytic
• a deletion mutant of alteplase with slower plasma clearance
• double bolus dosing rather than infusion:
  • give reteplase as double bolus injections over 2min, with 2nd bolus 30min after the 1st

• a triple-combination mutant of alteplase derived via recombinant DNA established from Chinese Hampster Ovary cells
• longer plasma half life (20min vs 7min and terminal half life is 130min)
• drug product info. sheet recommends lower heparin doses than are standard:
  • heparin 5000IU IV stat (4000IU if < 67kg) then infusion 25000IU in 500ml NS @ 16ml/hr (<67kg) or 20ml/hr (>67kg)
  • aim for aPTT of 50-75secs
• single IV bolus dose dependent on weight, given over 10sec else Mx as for tPA:
  • dosages marked on syringe in ml or kg:
    • <60kg: 6ml (ie. 30mg = 6,000IU) USE 40mg size ampoule!
    • 60-70kg: 7ml (ie. 35mg = 7,000IU) USE 40mg size ampoule!
    • 70-80kg: 8ml (ie. 40mg = 8,000IU) USE 40mg size ampoule!
    • 80-90kg: 9ml (ie. 45mg = 9,000IU) USE 50mg size ampoule!
    • >= 90kg: 10ml (ie. 50mg = 10,000IU) USE 50mg size ampoule!
• NB. incompatible with dextrose, use NSaline infusions only in that cannula concurrently
• more fibrin-specific than alteplase ⇒ less non-cerebral bleed & better mortality in subgroup of pts where Rx started > 4hrs
• less non-cerebral bleeding than r-TPA (ASSENT-2 trial)
• introduced in Aust. 2000
• single bolus tenectaplase (TNK) at dose of 0.25mg/kg appears to be non-inferior to alteplase for Mx of stroke:
  • easier to administer
  • longer half-life (3x as longer and even longer terminal half life)
  • more fibrin specific (14x)
  • less drop in systemic fibrinogen levels (10x)
  • more resistant to PAI-1 (80x)
  • more potent
  • less MMPp9 activation
  • possibly safer
  • less expensive
  • see thrombolysis in stroke

• within past 10 days:
  • active bleeding eg. GIT, genitourinary BUT not menstruation as compressible with vaginal packs
  • trauma
  • major surgery eg. CABG, obstetric delivery, organ Bx, puncture of noncompressible vessels
• known haemorrhagic diathesis
• thrombotic/haemorrhagic stroke CVA in last 6 months
• severe uncontrolled HT with systolic BP > 200 or diastolic BP > 110mmHg despite use of IV GTN
• SBE (eg. IV drug users with cocaine induced AMI)
• acute pericarditis
• high likelihood of left heart thrombus (eg. mitral stenosis with AF)
• see also specific C/Is to SK

• clinical evidence or history of TIA's
• concomitant use of oral anticoagulants with INR > 2
• prolonged (>10min) or traumatic CPR
• recent non-compressible vascular puncture eg. CVC
• pregnancy
• systolic BP > 175mmHg - consider angioplasty instead
• PH CABG as these patients may be relatively resistant to thrombolytic Rx & thus should be considered for direct angioplasty or combined thrombolytic Rx and rescue angioplasty
• haemorrhagic ophthalmic conditions eg. active diabetic haemorrhagic retinopathy

• see thrombolysis in stroke

• haemorrhagic stroke 0.5-1.0% (slightly more with tPA than with SK):
  • comparable to incidence of all types of stroke in AMI without thrombolytic Rx (mostly embolic)
  • if have haemorrhagic stroke during AMI then mortality increases from 12% to 47%
  • risk of haemorrhagic stroke:
    • 3.4% if PH CNS disease, TIA's or CVA
    • 0.5% if no PH neurologic disease
    • 0.5% with SK vs 1.0% with tPA
• systemic bleeding (slightly more with SK than with tPA):
  • GIT bleed or drop in h'crit by > 15% - 3% pts
  • minor bleeding 19%
• significant bleeding if given post-pulmonary angiography (14%)
• see Mx of bleeding (below)

• esp. with SK (12% vs tPA 7%) usually due to vasodilatation:
  • responds to IV fluids
  • if BP falls below 80mmHg:
    • place in Trendelenberg
    • consider IV fluid bolus
    • reduce infusion rate to half
  • if BP falls below 70mmHg:
    • cease infusion & recommence at half previous rate when BP > 70mmHg

• 1.5-20% in pts on SK
• Mx:
  • if mild-moderate:
    • promethazine 25mg IV &/or
    • hydrocortisone 100mg IV
  • if severe:
    • cease infusion immediately
    • adrenaline / epinephrine 1:10,000 1ml IV over 5min
    • if no response:
      • adrenaline / epinephrine 1:10,000 2-5ml IV over 5min, and,
      • promethazine 25mg IV &/or
      • hydrocortisone 100mg IV

• consider IV fluids & Trendelenberg position if hypotension

• local pressure
• IV fluid replacement
• cease thrombolytic &/or anticoagulant Rx
• maintain h'crit above 30% in pts with AMI & compromised coronary perfusion:
• blood transfusion prn
• if on heparin, give protamine sulphate 1mg per 100U of heparin may be given to decrease half-life of heparin from 90 to 45min
• if bleed causing haemodynamic compromise but not immediately life-threatening:
  • cryoprecipitate 6-8 units for a target fibrinogen level of 1g/L, then,
• if pt still bleeding then give 2-6U FFP
• if still bleeding, then 6-8U platelets
• if new focal neurologic deficits develop, or new headache or decreased GCS:
  • stop thrombolytic & anticoagulant Rx
  • protamine as above if on heparin
  • FFP if INR prolonged
  • urgent non-contrast CT brain scan
  • if intracranial bleed:
    • elevate head to 30 degrees— target PaCO2 35-40 mmHg
    • BP control e.g. SBP <160 mmHg and MAP <110 mmHg
    • urgent neurosurgical consult to decide on options vs palliation
      • consider mannitol or hypertonic saline to control raised ICP
    • inform parent unit (eg. stroke consultant if patient is a stroke patient)
    • monitor BP every 15min
    • FFP 2 units q6h for 24h
    • cryoprecipitate 10 units if not already given for a target fibrinogen level of 1g/L, then,
    • 1 adult bag platelets if not already given
    • DDAVP 0.3 microg/kg
    • if significant circulating thrombolytic levels then consider:
      • antifibrinolytics:
        • epsilon-aminocaproic acid 5g in 15-60min
          • inhibits activation of plasminogen
          • risk of serious thrombotic complications!
        • tranexamic acid 1g IV
    • fibrinogen levels should be rechecked every Q 4 hours & cryoprecipitate transfused PRN to maintain fibrinogen levels
    • rpt CT brain may be indicated to assess progression