Blood and Clots Series: What are the risks of reversing DOAC-associated intracranial bleeding?

In Blood & Clots, Medical Concepts by Andrew ShihLeave a Comment

CanMEDS Roles addressed: Medical Expert

Case Description

You are seeing a 54F in the emergency department after she sustained a mechanical fall. She struck her head on the pavement and is now confused.

Her comorbidities include: hypertension, diabetes mellitus, and atrial fibrillation.  She has been taking rivaroxaban 20 mg daily for three years without incident. Her complete blood count (CBC) demonstrates a white blood cell (WBC) count of 7.9 x 109/L, hemoglobin of 115 g/L, and platelet count of 145 x 109/L.  Prothrombin Time (PT) is 18 seconds (normal 11-13 seconds), activated partial thromboplastin time (aPTT) is 35 seconds (normal 30-40 seconds), and INR is 1.3 (normal 0.8-1.1). Her last dose of rivaroxaban was 6 hours ago.

A non-contrast CT scan of her head demonstrates a moderate-sized acute intracranial hemorrhage (ICH). Neurosurgery is consulted. In addition, you need to answer the following questions:

  1. What immediate steps should be taken to manage this patient’s rivaroxaban-associated ICH?
  2. Are any laboratory coagulation tests helpful in managing this patient?
  3. How should the anticoagulant effect of rivaroxaban be reversed, and what are the risks of these reversal options?


Direct oral anticoagulants (DOACs) are commonly used for stroke prevention in atrial fibrillation.  They have a favorable safety profile, with a meta-analysis demonstrating a 28% reduction in major bleeding, and approximate 50% reduction in intracranial and fatal bleeding 1.  However, this knowledge isn’t comforting to the emergency physician who is managing a patient with life-threatening DOAC-associated ICH!

  1. What immediate steps should be taken to manage this patient’s rivaroxaban-associated ICH?

First, consider the management of intracranial hemorrhage irrespective of anticoagulation, which may include:

  • Finding out what the patient’s wishes are: advance directives, family members, power of attorney, etc.
  • Discontinuing drugs that may contribute to bleeding
  • Supportive care in a monitored setting
  • Red blood cell transfusion as needed (usually to a restrictive target threshold of 70-80 g/L when possible)
  • Consulting surgical colleagues to assess if a definitive intervention can be performed
  • Considering adjunct treatments to bleeding such as antifibrinolytics (such as tranexamic acid, which has an excellent safety profile) and desmopressin
  1. Are any laboratory coagulation tests helpful in managing this patient?

Our patient’s coagulation profile is as follows:

  • Prothrombin Time (PT) is 18 sec (normal 11-13 sec)
  • aPTT 35 sec (30-40 sec)
  • INR 1.3 (0.8-1.1).

Conventional coagulation tests may be useful for excluding relevant drug levels, but should not be relied upon for management:

  • Dabigatran: APTT [activated partial thromboplastin time] (lacks sensitivity), TT [thrombin time] (too sensitive)
  • Rivaroxaban/Apixaban: PT [prothrombin time] is often prolonged; however, a normal PT does not exclude clinically important drug concentrations

In this case, our patient’s prolonged PT is consistent with her having having taken rivaroxaban; however, this information is not helpful in her management as one may assume she has clinically important rivaroxaban concentrations present if she has taken the medication within the past 12-24 hours (as the half-life of rivaroxaban is 8-12 hours).

Therefore, during acute major bleeding, do not wait for laboratory tests to come back before intervening!

Note that specialized coagulation tests are also available at select institutions for Dabigatran (Dilute TT, Ecarin Clotting Time) or Rivaroxaban/Apixaban (anti-Xa levels calibrated to each drug). However these are not typically available on an emergent basis and should not impact clinical care.

  1. How should the anticoagulant effects of rivaroxaban be reversed, and what are the risks of these reversal options?

Reversal should be considered in cases of moderate (such as subacute gastrointestinal bleeding or severe menorrhagia) or life-threatening bleeding; or if an emergent procedure/surgery is required.  There are generally two categories of reversal agents:

  1. Specific reversal agents
  2. Non-specific reversal agents

Specific reversal agents are the best option for DOAC reversal as they are targeted therapies with putatively greater efficacy and safety.  Some examples are shown in Table 1.

Table 1 – Specific Reversal Agents for the DOAC-anticoagulated Patient

Name of Specific Reversal Agent Key Details about this Reversal Agent Practical Considerations
  • Reverses direct thrombin inhibitors (dabigatran), factor Xa inhibitors, and heparins
  • Phase 2 study used 100-300 mg single intravenous dose
  • As of writing (January 2018), not approved by the US FDA, Health Canada, and the European Medicines agency
  • Requires further study in clinically bleeding patients
Andexanet Alfa
  • Reverses factor Xa inhibitors
  • Suggested dose: 800 mg bolus and 960 mg infusion over 2 h; patients who take apixaban or rivaroxaban more than 7 hours before andexanet administration: 400 mg bolus and 480 mg infusion over 2 hours
  • As of writing (January 2018), not approved by the US FDA, Health Canada, and the European Medicines agency
  • Short half-life – effects wear off in ~4 hours after bolus and infusion
  • Thrombosis observed in clinical studies, but unclear if related to drug or underlying disease
  • Associated with transient increase in D-dimer and prothrombin fragments (unknown clinical significance)
  • Reverses dabigatran
  • Suggested dose:  Total of 5 g given as two 2.5-g 50 mL boluses within 15 minutes of each other
  • Local availability may vary
  • May require readministration due to short half-life (47 minutes) though effect may last up to 12-24 hours
  • Thrombosis observed in clinical studies, but unclear if related to drug

Non-specific reversal agents refer to agents that may have some evidence of efficacy in DOAC reversal but are not specifically developed for this purpose (for example, prothrombin complex concentrates [PCCs] were developed to reverse warfarin).

Due to the lack of evidence in clinically bleeding patients, specific reversal agents, definitive interventions, and local hemostasis should be primarily used in DOAC-associated bleeding whenever possible. In addition, non-specific reversal agents are associated with adverse effects.

The main consideration for PCCs and aPCCs (activated PCCs) is thrombosis. The thrombotic risks of PCCs and aPCCs have not been studied in DOAC-associated bleeding. However, extrapolating from PCC use in vitamin K antagonist (ie warfarin) reversal and FEIBA use (often in hemophilia) may be a reasonable surrogate. Additionally, anticoagulants are often used in patients with thrombotic disorders, so it’s often unclear whether thrombosis has occurred due to the reversal agent or due to the underlying thrombotic disorder.

Examples of non-specific reversal agents and their limitations are shown in Table 2.

Table 2 – Non-specific Management Strategies & Reversal Agents for the DOAC-anticoagulated Patient

Name of Nonspecific Reversal Agent Key Details about this Reversal Agent Limitations or Cautions
Prothrombin Complex Concentrates (PCCs)
  • Available in 3- and 4-factor formulations.
  • Generally recommended dose is 25-50 U/kg
  • In a recent prospective cohort study, a median of 2000 units was used 2.  This can be infused over 20-30 minutes.  May consider an additional dose if still severely bleeding
  • Thrombosis risk observed in its use in patients on warfarin; reported risk of thromboembolism is 1.4% in meta-analysis of 27 studies 3.
  • A pooled analysis of two RCTs suggested the rate could be as high as 7.3% at 60 days after use of PCC, infusion for VKA-associated bleeding or urgent procedures, but no difference was shown compared to plasma 4.
Activated Prothrombin Complex Concentrates (aPCCs, FEIBA commonly used)
  • Generally used dose is 50 U/kg
  • Can be infused over 30-60 minutes.  May consider an additional dose if still severely bleeding
  • For hemophilia patients the thrombosis rate has been reported at a rate of 4-8 events per 10,000 infusions 5
Hemodialysis 6
  • Option for removal of dabigatran in patient’s plasma.
  • Rebound is common after renal replacement therapy is discontinued, likely due to redistribution from the extravascular space 7
  • Line-related complications such as bleeding and infection
Activated Charcoal
  • For dabigatran (within 2-3 hours of taking it) or apixaban (within 6 hours)
  • Useful only in acute setting.
  • No proven efficacy for other DOACs
  • Caution the use of this in patients with altered or decreased level of consciousness due to risk of aspiration.

Inappropriate Options for Intervention

Though it is tempting to consider the following options for reversal of DOACs, especially when the above reversal agents are not available, we would recommend against the options listed below. They have no proven efficacy from the literature and are associated with definite harm.

  • Frozen plasma is inappropriate for DOAC-associated bleeding since it lacks efficacy, giving unnecessary risk 8. The exception is in the setting of a massive transfusion protocol.
  • Platelet transfusions should be considered as if the patient was not on a DOAC. For example, this patient should not receive platelet transfusions as the platelet count is within normal range.
  • Recombinant factor VIIa does not correct many abnormalities in vitro for DOACs and has definite thrombotic risk.

Case Conclusion

You speak to the family who confirm that the patient took her rivaroxaban 6 hours ago. They wish for full resuscitation in the absence of an advance medical directive. After discussing the risks of reversing the rivaroxaban, the family agrees to it. You administer tranexamic acid and 2000 units of PCC, given that a specific antidote is not available. Despite this, intraventricular extension of the hemorrhage occurs and the patient develops hydrocephalus. She is taken to the OR for ventriculostomy and external ventricular drainage. The patient has a prolonged post-operative course in the ICU but is eventually discharged to rehabilitation.

Main Messages

  • When managing DOAC-associated bleeding, consider the interventions that you would perform if the patient was not on a DOAC.  Tranexamic acid has an excellent safety profile based on RCTs. Definitive procedural intervention remains the cornerstone of therapy.
  • Specific reversal agents should be used whenever possible. PCCs and FEIBA are options in factor Xa inhibitor associated bleeding in the absence of a specific reversal agent, where thrombosis risk is low but should be discussed during consent.
  • Plasma and platelet transfusion should only occur when indicated as if the patient was not on a DOAC.

This post was reviewed by Mark Woodcroft (@markwoodcroft), Teresa Chan (@TChanMD) and uploaded by Rebecca Dang


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Andrew Shih

Andrew Shih

Dr. Andrew Shih works as a Transfusion Medicine specialist at Vancouver Coastal Health Authority. His interests include education regarding the safety and appropriate utilization of blood products and advance blood transfusion as a personalized medical therapeutic intervention.