To assist clinicians in the management of bleeding in patients receiving a direct oral anticoagulant (DOAC).Four direct oral anticoagulants (DOACs; dabigatran, apixaban, edoxaban, and rivaroxaban) are approved for clinical use in Canada based on findings from large, randomized trials. Like all anticoagulants, bleeding is the major complication of DOAC therapy. Although the mainstay of bleeding management is supportive, a specific anticoagulant reversal agent is available for dabigatran (idarucizumab ). There are currently nonspecific reversal agents available for factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) available in Canada. The use of non-specific pro-hemostatic products (e.g. 4-factor prothrombin complex concentrate , activated PCC ) has been evaluated in small cohorts of DOAC-treated patients with major bleeding . Appropriate management in all cases of bleeding requires a systematic approach to assessing the competing risks and consequences of bleeding and thrombosis.# MANAGEMENT OF BLEEDING EPISODES:
Minor Bleeding (examples: extremity bruising, hemorrhoidal bleeding, subconjunctival bleed, self-limited epistaxis):
- Continue anticoagulant and monitor - Confirm the patient is receiving the appropriate drug and dose based on indication, age, weight, and creatinine clearance - Consider measuring hemoglobin, platelet count, creatinine, and liver function tests - Review concomitant medications which may contribute to bleeding (e.g. antiplatelet therapies, NSAIDs) 

# Clinically Relevant Nonmajor Bleeding

# Apixaban/Edoxaban/Rivaroxaban
- If apixaban/edoxaban/rivaroxaban is likely still present (as per time of last dose and creatinine clearance), give PCC. PCCs are not selective reversal agents, and their effect is debatable. If specific drug levels are rapidly available and less than 30-50 ng/mL, no treatment is required. - Inform patients/families regarding potential thrombotic risk in this setting due to interruption of anticoagulation, activation of coagulation to stop bleeding, and administration of PCC (e.g. stroke, myocardial infarction, and venous thromboembolism), but highlight that consequences of uncontrolled bleeding likely exceed this risk. - Consider adjunctive therapy with tranexamic acid for uncontrolled bleeding (limited data in this setting) - Note: Andexanet alfa is a specific antidote for factor Xa inhibitors but is not currently available in Canada. - >30 ng/mL = likely significant anticoagulant effect 1
- <30 ng/mL = likely no significant anticoagulant effect 1
- >30 ng/mL = likely significant anticoagulant effect 1 1 There are no data to establish a hemostatic threshold below which drug levels are unlikely to affect hemostasis. These estimates are extrapolated from observations in clinical trials and are in agreement with other guidelines.
Rule out other causes of increased PT/INR/PTT (e.g. DIC, coagulopathy of liver disease, vitamin K deficiency, warfarin, a coagulation factor inhibitor, or a factor deficiency). Notes regarding pro-hemostatic therapies (PCC, FEIBA, recombinant factor VIIa) for DOAC-associated severe/life-threatening bleeding:
- Supportive clinical data for pro-hemostatic agents (PCC, FEIBA, rVIIa) are limited and based on the results of several small observational cohorts of DOAC-treated bleeding patients, in vitro studies, animal models, and studies in human volunteers evaluating coagulation markers. - PCC (Octaplex, Beriplex) and activated PCC (FEIBA) are coagulation factor concentrates, not DOAC antidotes. They do not affect the inhibitory effect of DOACs on coagulation factors IIa (thrombin) and Xa, and they do not affect DOAC drug levels. These agents may reduce DOACassociated bleeding by providing large amounts of exogenous factors II and X. They may be associated with a small increased prothrombotic risk. - The use of antifibrinolytic agents such as tranexamic acid (Cyclokapron) and aminocaproic acid (Amicar) has no direct supporting evidence of benefit in patients with DOAC-associated bleeding. However, early use of tranexamic acid has benefit in traumatic bleeding, postpartum bleeding, and cardiac surgery and it has a good safety profile. Therefore, it may be considered as an adjunct for the treatment of DOAC-associated bleeding although specific data in this setting are lacking. - Recombinant factor VIIa (rFVIIa; NovoSeven, Niastase) is generally not recommended because of a lack of benefit in animal and in vitro studies and is associated with prothrombotic risk.

# WHEN BLEEDING HAS RESOLVED
- Assess patients for resumption of anticoagulation when hemostasis is achieved with consideration of patient values and preferences. Confirm ongoing indication for anticoagulation. 2. Estimate the risks of recurrent bleeding and thrombosis (and their clinical sequelae) with multidisciplinary input. 3. Assess baseline laboratory tests (hemoglobin, platelet count, creatinine, liver function tests) and current patient's weight.
- Review concomitant medications and reassess the need for medications which may contribute to bleeding (e.g. antiplatelet therapies, NSAIDs). 5. Confirm the appropriateness of the type and dose of anticoagulant based on clinical characteristics such as indication, age, weight, and creatinine clearance. 6. Provide education and counselling regarding bleeding complications and when to seek medical attention. 7. Ensure routine follow-up and reassessment of #1 to #6 at regular intervals.

# SPECIAL CONSIDERATIONS:

# Pediatrics
There are no studies evaluating the management of bleeding in children receiving DOACs.

# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Apixaban (Eliquis) - Dabigatran (Pradaxa) 

# Date of version: 29November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.