Dr (Prof) Sundeep Mishra discusses treatment protocol for major bleeding caused by oral anticoagulants, including the 4 "R" strategy and key points for individual OAC-associated bleeding.

More and more patients are getting treated for venous and arterial thrombosis of various types. However, treatment of these disorders with drugs; antithrombotics/anticoagulants is associated with the narrow therapeutic index. In other words, a low dose of these drugs is associated with thrombosis, while higher doses may lead to bleeding. Moreover, because many of these drugs are highly protein-bound, a slight change in internal milieu can change the serum levels of these drugs. Thus, treatment of patients presenting to the hospital with major bleeding is becoming more common and assumes significance in light of high morbidity and even associated mortality.

Risk of bleeding

The risk of a major bleeding event in AF patients treated with warfarin is 2-3% per year. Above 75 years old, the risk of intracranial haemorrhage (ICH) in patients taking warfarin increases significantly. The use of NOACs may decrease bleeding risk by ≥30% overall 7 ICH by 60% as also the risk of fatal haemorrhage, in comparison to warfarin. However, the risk of GI bleeding may be higher with NOACs (except apixaban).

Approach to management of oral anticoagulant-associated bleeding

Management of oral anticoagulation-associated bleeding involves 4 “R”: review, repair, reverse or replete, and resume.

1. Review: It involves the following steps-
   1. Withdraw anticoagulation:
      1. Stop the anticoagulation – it may be important to understand that because of the short half-life of some oral anticoagulants (NOACs), mere discontinuation of therapy may be enough for minor bleeds.
      2. Removal of the oral anticoagulant with gastric lavage/oral charcoal is good for conventional anticoagulants. However, NOACs are rapidly absorbed after oral administration, and activated charcoal can make airway management extremely difficult especially if the patient becomes unstable. Moreover, it makes endoscopy nearly impossible in patients with GI bleeding so it should be reserved for only very severe cases of NOAC bleeding.
      3. Dialysis - Dabigatran is dialysable and therefore haemodialysis can be used in some cases of dabigatran-related bleeding.
   2. Determine the time of the last dose
   3. Investigate the source of bleeding and perform other baseline laboratory values
   4. Review concomitant medications
   5. Evaluate the patient’s co-morbidities
   6. Assess for cardiac decompensation
   7. Maintain organ perfusion and if need be transfuse
2. Repair: It involves-
   1. Assessing the need for endoscopy, interventional radiology, or surgery
   2. Performing the appropriate procedure to stop the bleeding
3. Reverse: It includes the use of reversal agents, specific agents being,
   1. Dabigatran- Idarucizumab for dabigatran
   2. Apixaban & Rivoroxaban- Andexanet alfa
   3. VKA-associated bleeding-
      1. Prothrombin complex concentrate (PCCs) are pooled, virus-inactivated concentrates of human clotting factors. Four-factor PCCs (4FPCCs) contain the vitamin K–dependent coagulation factors [II (prothrombin), VII, IX, and X], and therapeutically effective concentrations of coagulation regulatory proteins (proteins C and S).
      2. Fresh frozen plasma (FFP) which were initially the treatment of choice but their use is limited by time requirements for thawing and cross-matching, concern for volume overload, and limited efficacy.
   4. Vitamin K infusion

These agents may be used for life-threatening bleeding, emergency surgery, and delayed clearance and bleeding.

4. Resume: It involves making an informed clinical decision about when to resume anticoagulant therapy based on the nature of the bleeding episode and the patient’s risk for a thromboembolic event.

Treatment of individual OACs

The replacement of blood components including red blood cells, platelets, and clotting factors is the critically important initial treatment for these individuals.

Coumadin induced bleeding:

1. Infusion of vitamin K helps to initiate the process of protein synthesis for the vitamin K–dependent coagulation proteins II, VII, IX, and X and the antithrombotic protein C and protein S.
2. Use of PCC (4-factor prothrombin complex concentrate), which includes factors II (prothrombin), VII, IX, and X and therapeutically effective concentrations of the regulatory proteins (protein C and S), provides real-time ability to slow bleeding. Dose - 4FPCC should be given in 2 separate 25 IU/kg doses, with a clinical evaluation performed after the first infusion and consideration of omitting the second if the patient is stabilised.

For dabigatran (thrombin inhibitor):

Idarucizumab, a highly specific antibody has been demonstrated to reverse the hypocoagulable state of the patient to allow blood clotting. Dose - The dose is 5 g in total, administered intravenously as 2 vials of 2.5 g in rapid succession.

Factor Xa anticoagulants apixaban and rivaroxaban:

1. Andexanet alfa is the highly specific agent for therapy, for patients treated with factor Xa inhibitors presenting with severe bleeding. Dose bolus 400 mg (delivered at the rate of 30 mg/min) followed by 4mg/min infusion over 120 min. Dose (and infusion) may be doubled if required.
2. If specific therapy is not available, replacement of lost blood components including red blood cells, platelets, and clotting factors and 4-factor prothrombin complex concentrate, or if not available, fresh frozen plasma can be tried.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Sundeep Mishra is a Professor of Cardiology.