ADD-ON / MEDICATION / ANTICOAGULANT THERAPY

Neutralization of the anticoagulant effects

Created 04/02/2022, last revision 21/03/2022

Indications for modification/discontinuation of anticoagulant therapy

  • interruption of anticoagulation in acute bleeding (included ICH)
    • ICH risk on VKA is 0.3-0.6%/year, on DOAC 0.1-0.2% [Schlunk, 2015]
    • anticoagulated patients (warfarin > DOAC) are at ↑ risk of prolonged bleeding (in about 30-50% of cases)   → spot sign in ICH
  • discontinuation of anticoagulation before administration of IV thrombolysis (→ see chapter on recanalization therapy in the anticoagulated patients)
  • discontinuation of anticoagulation before surgery
    • emergency surgery
    • elective procedure → see separate chapter
  • dose adjustment in case of overdose (according to laboratory tests)
    • applies mainly to warfarin

Categorization of bleeding complications

  • for the management of hemorrhagic complications it is essential to assess the severity of bleeding
Severe bleeding
  • decrease in Hb concentration ≥ 20 g/l
  • bleeding requiring blood transfusions (> 2 units)
  • symptomatic bleeding (intramuscular, retroperitoneal, intraocular)
  • bleeding manageable only by surgery
  • active bleeding from any source + hypotension (SBP < 90 mm Hg)
  • bleeding requiring hospitalization
Life-threatening bleeding
  • loss of whole blood volume within 24 hours (i.e., about 10 units of erythrocytes)
  • decrease in Hb concentration ≥ 50 g/l
  • loss of 50% of blood volume within 3 hours
  • continued blood loss exceeding 150 ml/minute
  • continued blood loss > 1.5 ml/kg/minute for more than 20 minutes
  • intracranial hemorrhage

LMWH

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Heparin

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Warfarin

  • significant bleeding →  check INR, administer IV Kanavit and start substitution therapy
  • asymptomatic overdose → proceed according to actual INR level
Warfarin overdose without bleeding
slight increase in INR
  • up to 10% of the upper limit of the therapeutic range
  • no high risk of bleeding
  • assess the possible causes of the increase (diet etc.)
  • return of INR to therapeutic range without change in warfarin dose is likely ⇒ maintain current warfarin dose
  • consider more frequent laboratory monitoring
INR 3,0-5,0
  • assess the possible causes of the overdose
  • reduce warfarin dose by 5-20% (based on calculated cumulative weekly dose) or omit warfarin dose
  • more frequent laboratory monitoring
  • INR gets in the therapeutic range within a few days
  • continue with a lower dose of warfarin once the INR is in the therapeutic range (5-20% reduction in warfarin dose)
INR 5,0 – 9,0
Low bleeding risk
  • skip one or two doses of warfarin, assess the cause of the overdose
  • consider more frequent laboratory monitoring
  • continue with a lower dose of warfarin once the INR is in the therapeutic range (5-20% reduction in warfarin dose)
High bleeding risk
  • skip one or two doses of warfarin, assess the cause of the overdose
  • KANAVIT gtt 1-5 drops per os
  • more frequent laboratory monitoring
  • continue with a lower dose of warfarin once the INR is in the therapeutic range (5-20% reduction in warfarin dose)
INR over 9,0
 
Low bleeding risk
  • discontinue warfarin therapy and assess the cause of the overdose
  • KANAVIT gtt 2-5 drops per os
  • frequent laboratory checks (no later than the following day)
  • if necessary, administer additional KANAVIT gtt
  • continue with a lower dose of warfarin once the INR is in the therapeutic range (5-20% dose reduction)
High bleeding risk
  • discontinue warfarin therapy and assess the cause of the overdose
  • KANAVIT gtt 5-10 drops per os
  • KANAVIT (amp/1ml/10mg ) 1/2-1 amp + 5 ml of NS as slow  IV injection ( 5 min)
  • frequent laboratory checks (every 6-12h)
  • continue with a lower dose of warfarin once the INR is in the therapeutic range (20% dose reduction)
any bleeding with subtherapeutic INR level
  • if the INR is in the subtherapeutic range (e.g., < 1.5), bleeding is probably caused by factors other than warfarinization
  • if in doubt, consult a hematologist

Effectiveness of therapies in correcting elevated INR

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Kanavit

KANAVIT (amp/1ml/10mg) 1/2-1 amp IV (dilute with 5 ml of NS or 5% glucose)

  • slowly inject over 5-10 minutes
  • effective after several hours
Substitution therapy

PROTHROMPLEX preferably

FRESH FROZEN PLASMA  10-15 ml/kg  in IV infusion

  • check INR after substitution and in 3-6h (after consumption of coagulation factors, INR may rise again), meanwhile the effect of Kanavit will start
  • repeat if necessary

DOAC

  • assess the severity of bleeding (mild, moderate, severe) and the patient’s general condition, especially BP, pulse, O2 saturation
  • take care of the source of bleeding, apply local hemostatic measures
    • mechanical compression, local hemostatics, endoscopic or surgical hemostasis
  • CBC +  coagulation tests (if available, order DOAC specific test)
    • consider transfusion in severe anemia →  see here
  • medical history:
    • medication, dose, time since last DOAC administration
    • estimate DOAC elimination time according to ClCr and coagulation test
    • other medications + comorbidities
  • replenish fluids
  • start hemodynamic support in case of major bleeding → shock see here
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Planned discontinuation of DOAC with respect to renal function and bleeding risk of procedure
Dabigatran Rivaroxaban / Apixaban / Edoxaban
bleeding risk
low
high
low
high
CrCl (ml/min)
≥ 80 ≥ 24h ≥48h ≥ 24h ≥48h
50-80 ≥ 36h ≥72h ≥ 24h ≥48h
30-50 ≥48h ≥96h ≥ 24h ≥48h
15-30 KI KI ≥ 36h ≥ 48h
<15 DOAC contraindicated
DOAC pharamacokinetics
Mild bleeding
  • postpone or skip the next dose
  • assess concomitant medication, verify indication for anticoagulation and correct dose (check renal functions)
Moderate bleeding
  • treat the source of bleeding
  • discontinue DOACs
  • consider antidote/substitution therapy (see below)
  • replenish the fluids and increase diuresis (mainly dabigatran is excreted in urine)
  • use activated charcoal if DOAC was administered in the previous 2 hours
  • administer platelets if thrombocytes  are < 60-80 x 109 /L
  • consider adjuvant therapy in coagulopathy/thrombocytopathies
    • EXACYL (tranexamová kyselina) 1g  IVR every 6h
    • OCTOSTIM (desmopresin acetát) 0.3 ug/kg +  100ml of NS  IV infusion over 15-30 minutes (maximal dose is 20 ug)
Severe, life-threatening bleeding
  • all above  +
  • antidote
  • if an antidote is not available, then start substitution therapy and/or hemodialysis (patient on dabigatran)

    • PCC (PROTHROMPLEX TOTAL NF) 50 IU/kg
    • aPCC (FEIBA NF)  25-50 UI/kg
  • hemofiltration via activated carbon
  • even after administration of the antidote, significant DOAC concentrations may reappear and lead to the recurrence of bleeding (more commonly after administration of andexanet alfa, less after administration of idarucizumab). It is, therefore, necessary to continue with clinical and laboratory monitoring of the patient
Elimination
  • activated charcoal (if DOAC was administered in less than 2-4h)
  • hemodialysis (for dabigatran, if no antidote is available)
    • severe bleeding + aPTT > 80 s or dTT > 400 ng/mL
Antidote
  • always use in life-threatening bleeding,  consider for major, non life-threatening bleeding as well  (EHRA 2018)
  • gatrans – the fast-acting antidote PRAXBIND (idarucizumab) → see here
  • xabans – ONDEXXYA (andexanet alfa) → see here
  • the universal antidote ARIPAZINE (ciraparantag) for xabans, gatrans, heparin, LMWH, fondaparinux is still in the testing phase
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Substitution therapy
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Follow-up procedures

  • regular checks of coagulation parameters (choose appropriate test according to the type of the anticoagulant)
    • if correction is sufficient, repeat the test in 4-6 hours
    • if correction is not sufficient, then consult a hematologist
  • in case of an overdose, assess the probable cause
    • comorbidities, interaction with other drugs, non-compliance
  • consider DVT prevention according to the degree of actual thromboembolic risk
    • intermittent pneumatic compression (IPC)
    • LMWH/UFH
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