ADD-ON / MEDICATION / ANTICOAGULANT THERAPY

Neutralization of the anticoagulant effects

David Goldemund M.D.
Updated on 21/03/2024, published on 04/02/2022

Indications for modification/discontinuation of anticoagulant therapy

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 that requires surgical intervention
  • active bleeding from any source + hypotension (SBP < 90 mm Hg)
  • bleeding requiring hospitalization
Life-threatening bleeding
  • loss of whole blood volume within 24 hours ( 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

Low molecular weight heparins (LMWHs)

  • protamine only partially neutralizes the anticoagulant effect of LMWH
    • ∼  60–75% of the anti-Xa activity of enoxaparin is neutralized; effectiveness depends on the specific LMWH agent used
  • dosing depends on timing since the last dose of LMWH (see table)

PROTAMIN

  • vial/5mL/50mg/5000IU + 100mL of NS administered by a short IV infusion (over 5-10 minutes
  • DO NOT EXCEED 5mg/minute !!
  • max dose 50 mg/10 min
  • dosing should ideally be guided by anti-Xa levels, if available
  • AEs: anaphylaxis, hypotension, bradycardia to arrest, flush
  • close monitoring is required, and protamine should be administered in a setting where emergency resuscitation measures are available
Protamine (amp = 1ml/10mg/1000IU)
nadroparin
(FRAXIPARIN)
1ml/9500IU
< 8 h
(since the last dose)
 6 mg/0,6mL for 950UI antiXA of nadroparin (0,1 ml)
> 8h do not use
enoxaparin
(CLEXANE, LOVENOX)
1ml/10000IU/100mg
 
< 8 h
10mg/1mL for 1000UI anti-Xa of enoxaparin (0,1 mL)
1 mg protamine per 1 mg enoxaparin
8-12 h
half dose
> 12h protamin likely not needed

Unfractioned heparin (UFH)

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Fondaparinux

  • fondaparinux (ARIXTRA) reversal is challenging because there is no specific antidote
  • andexanet alfa and protamin seem to be ineffective in neutralizing the anti-Xa effects of fondaparinux  (Siddiqui, 2019)
  • fondaparinux is not significantly removed by dialysis (due to its large molecular size and strong protein binding)
  • in cases of fondaparinux-related hemorrhage, consider coagulation factors supplementation; limited data are available on recombinant factor VIIa and PCC; both drugs may be used as off-label therapy

RECOMBINANT FACTOR VIIa

PROTHROMBIN COMPLEX CONCENTRATE

Argatroban and Bivalirudin

  • no approved reversal agent
  • reversal is likely not needed if 3-5 half-lives have elapsed
    • argatroban half-life 40-50 minutes
    • bivalirudin half-life 25 minutes (extends up to 3.5 hours in dialyzed patients)

RECOMBINANT FACTOR VIIa

Warfarin

  • significant bleeding →  check INR; if in therapeutic range, administer IV vitamin K + start substitution therapy
  • asymptomatic overdose → proceed according to current INR

Warfarin overdose without bleeding

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 the therapeutic range is likely without change in warfarin dose ⇒ maintain current warfarin dose
  • consider more frequent laboratory monitoring
INR 3 -5
  • assess possible causes of the overdose
  • reduce the warfarin dose by 5-20% (based on the calculated cumulative weekly dose) or omit the warfarin dose
  • more frequent laboratory monitoring
  • INR returns to 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 – 9
Low risk of bleeding
  • skip one or two doses of warfarin, assess possible 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 risk of bleeding
  • skip one or two doses of warfarin, assess possible cause of the overdose
  • KANAVIT GTT 1-5 drops per os
  • more frequent laboratory monitoring
  • continue with a reduced dose of warfarin once the INR is in the therapeutic range (5-20% reduction in warfarin dose)
INR over 9
 
Low risk of bleeding
  • discontinue warfarin therapy and assess possible causes of 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 reduced dose of warfarin once the INR is in the therapeutic range (5-20% dose reduction)
High risk of bleeding
  • discontinue warfarin therapy and assess the possible 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 minutes)
  • frequent laboratory checks (every 6-12 hours)
  • continue with a reduced dose of warfarin once the INR is in the therapeutic range (20% dose reduction)
any bleeding with a subtherapeutic INR level
  • if the INR is in the subtherapeutic range (e.g., < 1.5), the bleeding is probably caused by factors other than warfarin
  • if in doubt, consult a hematologist

Effectiveness of therapies for the correction of elevated INR

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Vitamin K

VITAMIN K (Phytonadione)

  • 1/2-1 vial (5-10 mg) dilute with 10 mL of NS or 5% glucose
  • slowly inject IV over 5-10 minutes
  • effective after several hours (usually used with substitution)
  • vitamin K acts as an antidote to warfarin by promoting the synthesis of clotting factors inhibited by the medication
  • intravenous or oral vitamin K administration can help reverse the anticoagulant effect of warfarin and restore normal blood clotting. The choice of route and dose of vitamin K depends on the severity of bleeding and the patient’s clinical condition
Substitution therapy
  • PCC is preferred to reverse warfarin

PROTHROMBIN COMPLEX CONCENTRATE

FRESH FROZEN PLASMA

Direct Oral Anticoagulants (DOACs)

  • assess the severity of the bleeding (mild, moderate, severe) and the patient’s general condition, especially blood pressure, pulse, O2 saturation
  • secure the source of bleeding, apply local hemostatic measures
    • mechanical compression, local hemostatics, endoscopic or surgical hemostasis
  • order CBC + coagulation tests (if available, request DOAC-specific tests)
    • consider transfusion for severe anemia
  • replenish fluids
  • start hemodynamic support in cases of major bleeding
  • obtain personal medical history:
    • medications+doses, time since the last DOAC administration
    • estimate DOAC elimination time according to ClCr and coagulation test results
    • other medications + comorbidities
  • antifibrinolytics (tranexamic acid or epsilon-aminocaproic acid) are considered off-label therapy for major DOAC-associated bleeding

Acute hemostasis testing in patients on DOACs

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Rough estimation of hemostasis normalisation after discontinuation of DOAC

Planned discontinuation of DOAC with regard to renal function and procedural bleeding risk
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

Therapy according to bleeding severity

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 (desmopressin acetát) 0.3 ug/kg +  100ml of NS  IV infusion over 15-30 minutes (the 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 oral charcoal (if DOAC was administered in < 2-4h)
  • hemodialysis (only for dabigatran if no antidote is available)
    • indications: severe bleeding + aPTT > 80 s or dTT > 400 ng/mL
Antidote
  • always use for life-threatening bleeding, consider for major, non-life-threatening bleeding as well  (EHRA 2018)

IDARUCIZUMAB  fast-acting antidote for dabigatran   → see here

ANDEXANET ALFA  antidote for apixaban, rivaroxaban and edoxaban → see here

CIRAPARANTAG  the universal antidote for DOACs, heparin, LMWH, and fondaparinux is still under investigation

Substitution therapy
  • preferably administer an antidote (especially for dabigatran); if not available, consider substitution therapy with 4-factor PCC:
    • anti-Xa levels / dTT > 30ng/ml [Steiner, 2017]
    • aPTT > 1.2 (if specific tests are not available)
  • the effect of substitution/elimination therapy cannot be expected with normal PT (rivaroxaban), aPTT, or dTT< 50ng/ml (dabigatran) ⇒  not indicated
  • use substitution therapy and andexanet alfa cautiously as they may cause thrombosis

PROTHROMBIN COMPLEX CONCENTRATE

RECOMBINANT FACTOR VIIa

Follow-up procedures

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

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Neutralization of the anticoagulant effects
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