Anticoagulation and Reversal of Anticoagulation

1. Supportive care: volume resuscitation, vasoactive agents if needed
2. Blood product transfusion
3. Identify bleeding source
4. Use of local hemostatic agents, mechanical compression, surgical intervention

1. FFP: Fresh Frozen Plasma
2. FVIIa: Recombinant Factor VIIa
3. DTI: Direct Thrombin Inhibitor
4. PCC: Prothrombin Complex Concentrate
5. LMWH: Low molecular weight heparin
6. DTI: Direct thrombin inhibitor

Pharmacologic Properties

1. Target: Factors II, VII, IX, X
2. Elimination half-life:
   • 20-60 hours (highly variable)
3. Duration of antithrombotic effect:
   • 2-5 days (dependent on repletion of clotting factors)

Reversal

1. Vitamin K (Phytonadione)
   • Oral is the preferred route of administration, time frame for effect: 24 hours
   • For emergent reversal or if unable to use oral administration, IVPB is the preferred parenteral route of administration, time frame for effect 12-16 hours, max rate 1mg/min
   • Subcutaneous/IM administration is not recommended due to erratic and/or incomplete absorption and potential for intramuscular bleeding (IM administration)
2. PCC and FVIIa have been shown to be effective in reversing the effect of warfarin but can increase the risk of thrombotic events; onset of INR reversal within 15 minutes.
   • FFP has been shown to be effective in reversing the effect of warfarin. Limitations of this agent can include potential for transmission of viral illness, longer preparation time, and large volume for administration.

*Use restricted to neurosurgery, stroke team (see member list in PCC guideline), emergency medicine, trauma, and hematology

Monitoring

1. Monitor of signs and symptoms of bleeding
2. Check PT/INR
   • 15 minutes after administration of FFP, PCC, or Factor VII
   • At 2 hours and every 6 hours thereafter
3. Repeat dosing not recommended

Pharmacologic Properties

1. Direct thrombin inhibitor (IIa)
2. Elimination half-life
   1. Healthy adults: 12-17 hours
   2. Severe renal dysfunction (CrCl 15-30ml/min): 27 hours
3. Duration of antithrombotic effect
   1. CrCl greater than 50ml/min: 1-2 days
   2. CrCl less than 50ml/min: 3-5 days

Reversal

1. Idarucizumab (Praxbind) is a humanized monoclonal antibody which binds directly to dabigatran and reverses its anticoagulant effects
2. It is unclear at this time if blood factor preparations (PCC, FVIIa) or blood products are useful for reversing the effect of dabigatran. Abnormal coagulation lab values may not be corrected with administration of hemostatic agents and may not be representative of clinical effect
3. Administration of PCC has not been shown to reverse abnormal coagulation lab values, however has demonstrated significant clinical hemostatic properties in murine model
   1. It is not recommended to use in combination with idarucizumab as it is not known to provide any additional benefit
4. FVIIa has demonstrated reversal of abnormal coagulation lab values in murine models, but did not demonstrate any significant improvement in clinical hemostasis in these models and is likely ineffective for reversal of this agent.
   1. It is not recommended to use in combination with idarucizumab as it is not known to provide any additional benefit

Monitoring

1. Monitor of signs and symptoms of bleeding
2. Anti IIa level should be sent on presentation to demonstrate presence of drug
3. PT/INR should not be evaluated given the insensitivity and variability of the assay in response to dabigatran

Pharmacologic Properties

1. Factor Xa inhibitor
2. Elimination half-life:
   1. Healthy adults: 5-9 hours
   2. Severe renal dysfunction (CrCl less than 30 ml/min): 9.5 hours
   3. Moderate hepatic impairment (Child-Pugh B): 10-12 hours
   4. Severe hepatic impairment (Child-Pugh C): No data
3. Duration of antithrombotic effect:
   1. Effect should dissipate in 4-5 half-lives

Reversal

1. Andexanet [Coagulation Factor Xa (recombinant) Inactivated-zhzo; Andexxa] is a recombinant, modified human factor Xa decoy protein that binds factor Xa inhibitors, reducing the ability of factor Xa inhibitors to act on endogenous Xa and restoring thrombin generation and normal coagulation.
2. It is unclear at this time if blood factor preparations (PCC, FVIIa) or blood products are useful for reversing the effect of rivaroxaban. There is limited data that suggests administration of PCC is effective at reversing abnormal coagulation lab values
3. There is no role for hemodialysis in the reversal of rivaroxaban

*Use restricted to neurosurgery, stroke team, emergency medicine, trauma, and hematology

**Use restricted to neurosurgery, stroke team, neurocritical care, or hematology approval. 

^#Use restricted to hematology and emergency department

Monitoring

1. Monitor of signs and symptoms of bleeding
2. Check PT 15 minutes after administration of hemostatic agent
3. INR should not be used

Pharmacologic Properties

1. Factor Xa inhibitor
2. Elimination half-life:
   • Healthy adults: 9-14 hours
   • Severe renal dysfunction (CrCl less than 30 ml/min): 17.3 hours
   • Severe hepatic impairment (Child-Pugh C): No data
3. Duration of antithrombotic effect:
   • Effect should dissipate about 24 hours after last dose

Reversal

1. Andexanet [Coagulation Factor Xa (recombinant) Inactivated-zhzo; Andexxa] is a recombinant, modified human factor Xa decoy protein that binds factor Xa inhibitors, reducing the ability of factor Xa inhibitors to act on endogenous Xa and restoring thrombin generation and normal coagulation.
2. It is unclear at this time if blood factor preparations (PCC, FVIIa) or blood products are useful for reversing the effect of apixaban.
3. There is no role for hemodialysis in the reversal of apixaban

*Use restricted to neurosurgery, stroke team, emergency medicine, trauma, and hematology

**Use restricted to neurosurgery, stroke team, neurocritical care, or hematology approval.    .^#Use restricted to hematology and emergency department

Monitoring

1. Monitor of signs and symptoms of bleeding
2. Check PT 15 minutes after administration of hemostatic agent
3. INR should not be used

Pharmacologic Properties

1. Utilizes ATIII to inhibit factors II and X
2. Elimination half-life: ~90 minutes (dose-dependent, increases with dose)
3. Duration of antithrombotic effect: 3-6 hours

Reversal

1. Due to the short half-life of heparin, most bleeding events can be managed by discontinuing administration
2. Protamine sulfate 1mg will neutralize the effects of approximately 100 units of heparin.
3. Heparin has a relatively short half-life of about 60–90 min when given as an IV infusion, and therefore only heparin given during the preceding several hours needs to be considered when calculating protamine doses.
4. The risk of severe reactions to protamine sulfate, such as hypotension and bradycardia, can be reduced by slow administration.
5. Protamine sulfate injection should be given by slow intravenous injection not to exceed a rate of 5mg/min.
6. Hemodialysis, FFP, vitamin K do not have a role in reversal

Monitoring

1. Monitor for signs and symptoms of bleeding
2. Repeat aPTT 15-30 minutes after protamine dose; subsequent protamine doses should be calculated accordingly

Pharmacologic Properties

1. Utilizes ATIII to inhibit factors II and X
2. Elimination half-life(enoxaparin):
   • Healthy adults: 4.5 – 7 hours
   • Renal impairment: 15 hours
3. Duration of Antithrombotic effect:

Reversal

1. Protamine sulfate neutralizes the anti-IIa activity, but has incomplete neutralization of anti-Xa activity.
2. Protamine 1mg neutralizes approximately 1mg of enoxaparin.
3. The risk of severe reactions to protamine sulfate, such as hypotension and bradycardia, can be reduced by slow administration.
4. Protamine sulfate injection should be given by slow intravenous injection at a rate not to exceed 5mg/min.
5. Hemodialysis, FFP, vitamin K do not have a role in reversal

Monitoring

1. Monitor for signs and symptoms of bleeding
2. PT/INR and aPTT are insensitive measures of therapeutic enoxaparin, however aPTT can be used in cases of overdose or to assess response to protamine as well.
3. Anti-Xa level can be assessed to determine residual anticoagulant effect, however protamine sulfate neutralizes only a variable portion of anti-Xa activity and clinical significance of this is unclear

Pharmacologic Properties

1. Directly inhibit thrombin (Factor IIa)
2. Elimination half-life
   • Argatroban: 45 min, prolonged in liver dysfunction
   • Bivalrudin: 25 min, prolonged in renal dysfunction

Reversal

1. No specific antidotes are available

# Feiba NF dosing: 50-100 units/kg (maximum 200 units/kg /day), use restricted to Hematology and Emergency Department

Monitoring

1. aPTT can be monitored to determine duration of anticoagulation effect

Pharmacologic Properties

1. Factor Xa inhibitor
2. Elimination half-life:
   • Healthy adults: 17-21 hours
   • CrCl less than 30ml/min: 39-46 hours
3. Duration of antithrombotic effect
   • 2-5 days, prolonged in kidney dysfunction

Reversal

1. No specific antidotes are available
2. There is limited data to support that Factor VIIa may have some benefit in the reversal of fondaparinux
3. There is no role for Vitamin K, protamine, or hemodialysis in the reversal of fondaparinux

# Feiba NF dosing: 50-100 units/kg (maximum 200 units/kg /day), use restricted to Hematology and Emergency Department

Monitoring

1. Monitor for signs and symptoms of bleeding
2. aPTT and PT/INR are insensitive measures of activity of fondaparinux