ACEP ID:

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How to Treat Anticoagulation-Associated Life-Threatening Bleeding

Section IconR: Recognize
Recognize the patient is bleeding or needs emergent surgery
Is the patient bleeding?
  • Provide Emergent Treatment/Supportive Care
  • If yes, is the bleed life threatening or at a critical site?
If non-bleeding, does the patient need emergent surgery/urgent procedure? (See “Emergency Surgery or Urgent Procedure” definition in “Verify life threatening or critical site bleed”)
Section IconE: Emergent
Emergent supportive care
Airway, breathing and circulation assessment
Source control: compression/tourniquet/surgery/interventionalists (e.g., Interventional Radiology/endoscopy)
Establish intravenous access: two or more 18g or larger peripheral IV>central line at compressible site>intraosseous line if transfusion anticipated
  • Consider US-guided IV if unable to place via standard methods
Send labs (PT/INR, PTT, CBC, CMP) and ECT/dTT/TT (dabigatran only)
Intravenous fluids
Blood products: send type and screen, crossmatch if transfusion anticipated; consider uncrossed PRBC in an unstable patient; potential massive transfusion protocol
Optimize comorbidities: uremia, liver disease, thrombocytopenia
Hold anticoagulation, antiplatelet agents
Charcoal: consider in overdose within 1-2 hours of ingestion of an oral anticoagulant
Desmopressin: consider for antiplatelet therapy
Tranexamic acid: consider topical/nebulized for ear, nose or throat, bleeding or intravenous for traumatic or gynecologic bleeding
Section IconV: Verify
Verify life threatening or critical site bleed
Life-threatening bleed
Composite of BARC type 3a & 3b definition:
  • Hemoglobin drop ≥5 g/dL from a recent (premorbid) known value (provided hemoglobin drop is related to bleed) PLUS transfusion OR
  • Uncontrolled bleeding requiring procedural intervention (e.g. intervention radiology, endoscopic, surgical*) OR
  • Hemodynamic instability: bleeding requiring intravenous vasoactive agents
    • *Excluding dental/nasal/skin/hemorrhoid
Critical Sites
Brain*
Eye**
Spine
Airway
Pericardium
Aorta
Closed space with concern for compartment syndrome
  • *Does not include microbleeds or hemorrhagic transformation
  • **Intraocular with vision compromise
Emergent surgery or Urgent Procedure
Invasive procedure with significant risk of life-threatening bleeding or bleeding at critical site that cannot be reasonably delayed beyond the length of the anticoagulant’s therapeutic effect (ie, >2 half-lives depending on clinical scenario) while empiric medical treatment is delivered
Section IconE: Elicit
Elicit anticoagulant agent use & last dose
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Class
Direct Thrombin Inhibitor
Anti-Xa Inhibitor
Anti-Medicated Inhibition of Xa
Inhibition of Thrombin: Indirectly Inactivates Xa
Vitamin K Antagonist

Agent/
Last Dose

Dabigatran
(<8-12 h)

Rivaroxaban/Apixaban
(<8-12 h)

Edoxaban
(10-14 h)

Fondaparinux
(17-21 h)

Unfractionated Heparin
(PTT based)
(1-2 h)

Enoxaparin/dalteparin
(3-5 h)

Warfarin
(INR based)
(20-60 h)

*Betrixaban was removed from market 4/2020

Section IconR: Reversal/Replacement
Reversal/Replacement agent specific
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Class
Direct Thrombin Inhibitor
Anti-Xa Inhibitor
Anti-Medicated Inhibition of Xa
Inhibition of Thrombin: Indirectly Inactivates Xa
Vitamin K Antagonist

Agent/
Last Dose/
Tier 1/
Tier 2c

Dabigatran
(<8-12 h)
Tier 1: Idarucizumab
Tier 2: PCCd dialysis

Rivaroxaban/Apixaban
(<8-12 h)
Tier 1: Andexanet alfaa
Tier 2: PCCd

Edoxaban
(10-14 h)
Tier 1: Andexanet alfab
Tier 2: PCCd

Fondaparinux
(17-21 h)
Tier 1: 4F-PCC
Tier 2: PCCd

Unfractionated Heparin
(PTT based)
(1-2 h)
Tier 1: Protamine

Enoxaparin/dalteparin
(3-5 h)
Tier 1: Protamine

Warfarin
(INR based)
(20-60 h)
Tier 1: Vit K and 4F-PCC
Tier 2: PCCd FFP

Tier 1 is preferred treatment. Tier 2 recommended only when tier 1 agents not available

aFor bleed only; bNot FDA approved; cIf Tier 1 not available; dIncludes: 4F-PCC (preferred), 3F-PCC, and aPCC; eFDA approved for bleeding only (not emergency surgery/urgent procedure). AT, antithrombin; FFP, fresh frozen plasma; PCC, prothrombin complex concentrate.

Section IconS: Supply
Supply correct dosage of reversal/replacement agent
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idarucizumab

direct thrombin (factor IIa) inhibitor (dabigatran)

<8-12 hours

humanized monoclonal antibody fragment, neutralizes the anticoagulant effect of dabigatran by irreversibly binding to it and its metabolites

1) Life threatening bleeding
2) Need emergency surgery/urgent invasive procedure
Specific for idarucizumab

9.5-10.8h

5g (2 vials) IV bolus

redosing was used in ~2% of patients
~$4,452 per administration

andexanet alfa

direct factor Xa inhibitors (apixaban and rivaroxaban)

<8-12 hours

recombinant modified human factor Xa (activated factor X) molecule, which acts as a decoy by reversibly binding to factor Xa inhibitors, thereby reducing their availability to act on endogenous factor Xa

1) Life threatening or uncontrolled bleeding
Specific for direct factor Xa inhibitors, approved only for apixaban and rivaroxaban

5-7h

Low dose 5 vials
≥8h since last dose or ≤5mg of apixaban or ≤10mg of rivaroxaban
Initial IV bolus: 400mg IV; target infusion rate of 30mg/min
THEN IV infusion: 4mg/min IV for up to 120 min
High dose 9 vials:
<8h since last dose or unknown AND >5mg of apixaban or >10mg of rivaroxaban
Initial IV bolus: 800mg IV; target infusion rate of 30mg/min; THEN IV infusion: 8mg/min IV for up to 120 min

low versus high dose based on timing from last dose and dosage amount of Xa inhibitor
Low dose: ~$12,500 per administration
High dose: ~$25,000 per administration

protamine

UFH and LMWH (enoxaparin, dalteparin)

1-6 hours (unfractionated heparin) – SQ doses of UFH take longer to absorb
3-12 hours (low molecular weight heparin) SQ doses of LMWH take longer to absorb

a weak anticoagulant which binds heparin & forms inactive complex

neutralization of heparin or low-molecular weight heparin

 

Heparin: 1mg of protamine will neutralize not less than 100 units of heparin; slow IV injection over 10 minutes up to MAX of 50mg per dose
Dalteparin: 1mg IV for every 100 anti-Xa IU of dalteparin
Enoxaparin: 1mg IV for every 1mg of enoxaparin administered in the previous 8h; if >8h has elapsed since the last dose a 2nd infusion of 0.5mg per 1 mg of enoxaparin may be given

~$10 to $133 per administration (50-450 mg range with higher range representing average dosing in cardiothoracic surgery patients for UFH reversal)

REPLACEMENT

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4-factor PCC***
(KCentra in the US)

approved use: vitamin K antagonists (warfarin)
non-approved use: DOACs

varies

contains non-activated vitamin K-dependent coagulation factors II, VII, IX, X, and antithrombotic protein C and protein S, heparin, albumin

urgent reversal of vitamin K antagonist therapy for treatment of major bleeding and/or surgical procedures

factor dependent: 4.2-59.7h

Warfarin:
Individualize dose by INR & IBW: INR-based 25-50 IU /kg IV, max 2500-5000 IU with concurrent Vitamin K
OR
****Fixed Dose
1500 IU x 1; may repeat 500 units if bleeding continues
DOACs:
Life-threatening or critical site:
10-25 units/kg. May consider 50 units/kg up to a suggested maximum of 100 units/kg
Non-life threatening or non-critical site: 10 units/kg x 1

warfarin: co-administer with IV vitamin K
DOAC: a median (interquartile range)
dose of 2000 IU (1500-2000 IU) less or more than 65kg respectively contains heparin so should not be used in patients with confirmed or strongly suspected HIT
~$5,075 to $20,300 per administration (25-100 units/kg = 1,750 – 7,000 units)

vitamin K

vitamin K antagonists (warfarin)

varies

vitamin necessary for the hepatic synthesis of factors II, VII, IX and X
cofactor for a microsomal enzyme that triggers the post-translational carboxylation of peptide-bound glutamic acid residues into active coagulation factor

acquired hypoprothrombinemia and anticoagulant reversal

n/a

non-bleeding patients: 2.5 to 25mg PO to lower INR
major bleeding: 5 to 10mg slow IV injection, in addition to 4-factor PCC

initial onset typically 3-6 hours if given IV and maximal initial effect on INR usually occurs around 16-20 hours.
for warfarin bleeding patients, give Vitamin K first and prior to 4F-PCC (Kcentra) if 4F-PCC used
Oral: ~ $67 to $353 per administration (5-25 mg PO)
IV: $135 to $270 per administration (5-10 mg IV)

fresh frozen plasma

vitamin K antagonists (warfarin)

varies

comprised plasma proteins such as albumin, immunoglobulins, coagulation factors, complement proteins and protease inhibitors

acquired combined coagulation factor deficiency, due to liver disease or undergoing cardiac surgery or liver transplant
TTP

n/a

10 to 15mL/kg IV for replacement of coagulation factors in patients with acquired deficiencies

thawing requires 15-30 minutes depending on the quantity
likely ineffective for DOAC reversal
~$168 per administration (4 units)

OTHER

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tranexamic acid

not drug specific

n/a

competitive inhibitor of plasminogen activation

IV: patients with hemophilia for short-term use to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction
Oral: heavy cyclic menstrual bleeding

IV: 2h
PO: 11h

Trauma: 1000mg administered IV over 10 minutes, followed by 1000mg infused over the subsequent 8 hours

~$18 to $174 per administration (1,000-2,000 mg)

aPCC = activated prothrombin complex concentrate, DOAC = direct oral anticoagulant, INR = International Normalized Ratio, IU = international unit, IV = intravenous, LMWH = low molecular weight heparin, PCC = prothrombin complex concentrate, PO = per os (by mouth), SQ = subcutaneous, TTP = Thrombotic thrombocytopenic purpura, UFH = unfractionated heparin, US = United States

*Assumes normal renal and hepatic function, normal body mass index,

**Cost based on typical initial administration for 70kg patient based on Medi-Span Average Wholesale Price as of June 2019. FFP price based on cost of $41.95 per unit from: Shander A, Ozawa S, Hofmann A. Activity-based costs of plasma transfusions in medical and surgical inpatients at a US hospital. Vox sanguinis. 2016;111:55-61.

***Dosing of PCC/aPCC products is expressed as units of factor IX

****Off-label

Section IconE: Evaluate
Evaluate scenario again
Reassess: Clinical, Labs, Imaging
Review supportive care measures (view list in “Emergent supportive care”)
Consultant recommendations
Is the patient stabilizing or improving?
  • Yes: move to disposition
  • No: escalate care – interventional radiology, endoscopy, surgery, consider alternate etiologies or sources
Section IconD: Disposition
Disposition patient
Clinical deterioration and role for redosing?
  • Yes: Consider Redosing & Admit/Transfer to Hospital or Procedural Area for Source Control
  • No: Admit/Transfer to Hospital or Procedural Area for Source Control
Reversal unnecessary and patient stabilized in ED?
  • Consider Observation or Discharge
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Acknowledgments

Developed by the ACEP Expert Panel on Reversal Agents

CONTRIBUTORS
Christopher W. Baugh, MD, MBA, FACEP (co-chair) James Williams, DO, MS, FACEP (co-chair) David Cornutt, MD; Alan Jacobson, MD Michael Levine, MD Charles E. Mahan, PharmD, PhC Evie Marcolini, MD, FACEP, FCCM John McManus, MD, MBA Truman J. Milling, Jr. MD, FACEP W. Frank Peacock, MD, FACC, FESC, FACEP Rachel P. Rosovsky, MD, MPH Ravi Sarode, MD Alex C. Spyropoulos, MD Jason W. Wilson, MD, MBA, FACEP Fred Wu, MHS, PA-C

 

ACEP Staff
Riane V. Gay, MPA, CAE Liz Muth, CAE Sandy Schneider, MD, FACEP

 

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