• Bleeding is a known complication of DOAC therapy
  
  • apixaban, dabigatran, edoxaban and rivaroxaban
• Grading of bleeding severity helps guide management and assess response
• The mainstay of bleeding management is supportive plus often includes the antifibrinolytic medication tranexamic acid
• Specific anticoagulant reversal agents are available;
  
  • for dabigatran - idarucizumab (Praxbind^®)
  • for apixaban and rivaroxaban - andexanet alfa (Ondexxya^®) in specific situations only, otherwise prothrombin complex concentrate - PCC (Octaplex^®)

• Grade bleeding severity according to modified world health organisation (WHO) bleeding score (grades 1-4)
• Alternatively, bleeding severity can be classified as major, significant non-major, or minor bleeding

WHO bleeding score

• WHO grade 4
  
  • debilitating bleeding including retinal bleeding and visual impairment 
  • non-fatal cerebral bleeding with neurological signs and symptoms 
  • bleeding associated with haemodynamic instability (hypotension, >30 mmHg change in systolic or diastolic blood
  • pressure) 
  • fatal bleeding from any source
• WHO grade 3
  
  • bleeding requiring red cell transfusion specifically for support of bleeding within 24 hr of onset and without
  • haemodynamic instability
  • bleeding in body cavity - fluids grossly visible 
  • cerebral bleeding noted on computed tomography (CT) without neurological signs and symptoms 
• WHO grade 2
  
  • melaena, haematemesis, haemoptysis, fresh blood in stool, musculoskeletal bleeding, or soft tissue bleeding not
  • requiring red cell transfusion within 24 hr of onset and without haemodynamic instability
  • symptomatic oral blood blisters, i.e. 
  • bleeding/causing major discomfort 
  • multiple bruises, each >2 cm or any one >10 cm
  • petechiae/purpura that is diffuse
  • visible blood in urine
  • abnormal bleeding from invasive or procedure sites
  • unexpected vaginal bleeding saturating >2 pads in a 24 hr period
  • bleeding in cavity - fluids evident macroscopically
  • retinal haemorrhage without visual impairment
• WHO grade 1
  
  • petechiae/purpura localised to 1 or 2 dependent sites, or sparse/non-confluent 
  • oropharyngeal bleeding
  • epistaxis <30 min duration

Major bleeding

• Bleeding requiring hospitalisation and at least one of the following;
  
  • death
  • symptomatic bleeding in a critical area or organ e.g. intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome
  • bleeding causing a fall in haemoglobin of 20g/L or greater
  • bleeding leading to transfusion of 2 units or more of red cells

Significant non-major bleeding

• Bleeding requiring medical attention and/or intervention e.g.
  
  • haemodynamically stable gastrointestinal bleed
  • epistaxis, haematuria, or menstrual bleeding

Minor bleeding

• Bleeding NOT requiring medical attention and/or intervention e.g.
  
  • extremity bruising, haemorrhoid bleeding, sub-conjunctival bleed, self-limited epistaxis 

Assess, Stop bleeding and Resuscitate

• Apply all possible local haemostatic measures (e.g. compression, packing, splinting)
• Grade severity of bleeding using WHO bleeding score and document in medical records
• If major bleeding, establish venous access and initiate resuscitation in a monitored setting
• In life-threatening bleeding, delaying reversal agent administration until coagulation test results are available may be detrimental

Send Urgent Investigations

• FBC, U&E, LFT, INR, APTT, Thrombin time (TT), Fibrinogen
• Group & screen (G&S) or crossmatch (XM) as clinically appropriate
• Alert haematology laboratory informing of urgency of samples

Major bleeding

• Consider anti-Xa - discuss with haematology
• Consider DOAC level - discuss with haematology

Interpretation

• Normal values of INR, APTT, TT* or Fibrinogen do not exclude anticoagulant effect/nor reflect level of anticoagulation
  
  • * excluding dabigatran, where normal TT demonstrates no significant anticoagulant effect
• Degree of PT/APTT prolongation does not correlate with bleeding risk 
• In patients on apixaban/edoxaban/rivaroxaban, if anti Xa level <0.2/mL then unlikely significant anticoagulant effect 

Assess anti-coagulation

• Confirm anticoagulant drug, dose and time since last dose
• Check patient body weight, calculate creatinine clearance (CrCL), (https://www.mdcalc.com/calc/43/creatinine-clearance-cockcroft-gault-equation).
• Using time of last dose, drug half-life and CrCl, determine the likely presence of the DOAC and the expected elimination rate. See SPECIFIC DOACs below
• Establish the indication for anticoagulation (where possible)
• Establish the indication for anticoagulation (where possible)
  • if VTE, date of previous VTE(s)/site(s)/provoking factors
  • if AF, CHA₂DS₂VASc score
  • if metallic heart valve, site/brand/surgery year
• Check if on concomitant antiplatelet agentsdate/type of cardiac stent
  • if cardiac stent, date/type

Creatinine clearance using actual body weight

• Use online calculator (e.g. https://www.mdcalc.com/calc/43/creatinine-clearance-cockcroft-gault-equation)

Manage cause of bleeding

• Arrange further investigation and definitive management e.g. 
  
  • endoscopy, interventional radiology, neurosurgery

• Withhold further anticoagulant therapy
• Establish venous access, initiate resuscitation in monitored setting
• Except in urinary tract & upper GI bleeding, give tranexamic acid (TXA) 1 g IV (slow IV injection)
• Follow with tranexamic acid 1g IV over 8 hours - caution with renal impairment - see SPC

Blood component transfusion

• Refer to major haemorrhage protocol (MHP) if appropriate
• Consider red cell transfusion as per clinical situation, adopting restrictive transfusion thresholds especially in GI bleeding
  • in absence of haemodynamic instability do not transfuse more >2 units red cells without checking Hb increment
  • if platelet count <50 x 10⁹/L (<100 x 10⁹/L if multiple trauma, traumatic brain injury or spontaneous intracerebral haemorrhage), transfuse 1 ATD platelets

Consider reversal agent

• Consider bleeding location and severity
• Estimate degree of anticoagulant exposure
• All DOACs are cleared to some extent by the kidneys, and their half-lives are best estimated by measuring the serum creatinine and calculating the creatinine clearance.
• If the last dose of a DOAC was taken 24 h previously in patients with normal renal function (CrCl>60ml/min), reversal agent unlikely to be necessary
• When the creatinine clearance is <30 mL/min, half-lives are prolonged and delayed clearance may be an indication for reversal if the patient has on-going bleeding
• After 3−5 half-lives anticoagulation effect likely to be insignificant, as 87.5−97% clearance

Rebleeding

• In patients experiencing re-bleeding, discuss a second dose of reversal agent (PCC/idarucizumab) with clinical haematology BEFORE administration 

Reversal agent to use

See SPECIFIC DOACs below

• Withhold further anticoagulant therapy
• Arrange further investigation and definitive management e.g.
  • endoscopy, interventional radiology, neurosurgery

Blood component transfusion

• For symptomatic anaemia excluding mild symptoms, consider single-unit RBC transfusion +/- intravenous iron (IVFe) 
• If platelet count <30 x 10⁹/L, consider platelet transfusion

Consider reversal agent

• If last dose of a DOAC was taken 24 hr previously in patients with normal renal function (CrCl >60 mL/min), reversal agent unlikely to be necessary
• Consult consultant haematologist on call for advice prior to reversal agent administration

• Confirm anticoagulant drug, dose, intensity, duration is appropriate for indication, age, weight, renal and liver functions
• Check FBC, U&E, LFT to ensure they are stable
• Review concomitant medications which may contribute to bleeding e.g. antiplatelet agents
• If bleeding stops, patient can restart anticoagulation with closer follow-up
• Advise patient to report to GP or Anticoagulation service if recurrent bleeding
• If recurrent minor bleeding, consider local intervention (e.g. haemorrhoid banding, nasal packing) 
• Consider temporary anticoagulation interruption provided low thrombosis risk

DOAC pharmacokinetics, effect on coagulation tests & ‘reversal’ agent

Select DOAC

• Complete local report for anticoagulation related major or clinically significant non-major bleeding (WHO grade 2 or above)
• Inform local anticoagulation service with patient details and outcome
• Discuss with haematologist regarding restarting anticoagulation
  
  • patient may be offered a different anticoagulant or dose, depending on risk of recurrent bleeding, renal function and patient preference
• Ensure patient is well informed about the treatment options, risks and benefits of restarting anticoagulation
• Advise patient to report immediately if any sign of recurrent bleeding
• Ensure discharge letter has clear advice for GP on when to restart anticoagulation, choice of anticoagulant treatment, dose and instructions for monitoring for further bleeding