What medications are used as bleeding inhibitors?

Medications Used as Bleeding Inhibitors

The primary medications used as bleeding inhibitors include reversal agents for anticoagulants (idarucizumab, andexanet alfa), bypassing agents for hemophilia with inhibitors (recombinant factor VIIa, activated prothrombin complex concentrates), and antifibrinolytic agents (tranexamic acid). 1

Anticoagulant Reversal Agents

For Vitamin K Antagonists (e.g., Warfarin)

• Four-factor prothrombin complex concentrate (4F-PCC) is the first-line reversal agent for vitamin K antagonists, with dosing based on INR:
  • INR 2 to <4: 25 units/kg
  • INR 4-6: 35 units/kg
  • INR >6: 50 units/kg 1
• Alternative fixed-dose options include 1000 units for non-intracranial major bleeding or 1500 units for intracranial hemorrhage 1
• Vitamin K (5-10 mg IV) should always be administered alongside PCC when reversing warfarin 1

For Direct Thrombin Inhibitors (e.g., Dabigatran)

• Idarucizumab (5g IV) is the specific reversal agent for dabigatran 1
• If idarucizumab is unavailable, PCC or activated PCC can be used as alternatives 1
• For recent ingestion (within 2-4 hours), activated charcoal should be considered 1

For Factor Xa Inhibitors (e.g., Apixaban, Rivaroxaban)

• Andexanet alfa is the specific reversal agent for factor Xa inhibitors 1
• Dosing depends on the specific Xa inhibitor, timing of last dose, and dose amount:
  • Low dose: 400 mg IV bolus followed by 4 mg/min infusion for up to 120 minutes
  • High dose: 800 mg IV bolus followed by 8 mg/min infusion for up to 120 minutes 1
• If andexanet alfa is unavailable, PCC or activated PCC can be used 1
• For recent ingestion (within 2-4 hours), activated charcoal should be considered 1

Hemophilia Management with Inhibitors

Bypassing Agents

• Recombinant Factor VIIa (rFVIIa, eptacog alfa) is a primary bypassing agent for hemophilia patients with inhibitors 1, 2

  • For joint bleeding: either 3 doses of 90 μg/kg at 3-hour intervals or a single dose of 270 μg/kg 1
  • Median dose for bleeding episodes and surgical procedures is 90 μg/kg with median interval between doses of 3 hours 2

• Activated Prothrombin Complex Concentrate (aPCC) is another option for patients with hemophilia and inhibitors 1

  • Caution: When used with emicizumab, there are dosing restrictions due to risk of thrombosis 1

Newer Agents

• Emicizumab is a bispecific antibody that mimics factor VIII function, used for prophylaxis in hemophilia A patients with inhibitors 1, 3
• Other emerging therapies include:
  • Concizumab and marstacimab (anti-tissue factor pathway inhibitor antibodies)
  • Fitusiran (small interfering RNA targeting antithrombin) 3

Antifibrinolytic Agents

Tranexamic Acid

• Mechanism: Synthetic lysine derivative that blocks plasminogen binding sites, inhibiting fibrinolysis 4
• Dosing: Commonly 10 mg/kg followed by infusion of 1 mg/kg/hour IV 4
• Applications:
  • Surgical bleeding: Reduces postoperative blood loss by 29-54% 4
  • Trauma: Reduces mortality by approximately one-third 5
  • Upper GI bleeding: Associated with 40% reduction in mortality 4
  • Menorrhagia: Reduces menstrual blood loss by 34-58% 4, 6
  • Dental procedures in patients on anticoagulants (as mouthwash) 4
  • As adjunct therapy in minor surgery for hemophilia patients with inhibitors 1

Clinical Considerations and Pitfalls

• For patients on anticoagulants with major bleeding, reversal agents should be administered promptly based on the specific anticoagulant 1
• When using PCCs to reverse VKAs, vitamin K should always be co-administered 1
• For hemophilia patients with inhibitors, treatment should be individualized based on:
  • Previous response to bypassing agents
  • Type of bleeding episode
  • Concomitant use of emicizumab (if applicable) 1
• For tranexamic acid, higher doses do not appear to increase efficacy but may increase risk of neurological side effects; a 1g IV dose is generally sufficient for maximal efficacy in adults 5
• Contrary to theoretical concerns, tranexamic acid has not been shown to increase thrombotic events in clinical trials and may actually reduce myocardial infarction risk in trauma patients 5

Special Populations

• Hemophilia B patients with inhibitors:

  • Extremely rare and challenging to manage
  • Risk of allergic reactions including anaphylaxis with FIX-containing products
  • Emerging non-factor therapies (concizumab, marstacimab, fitusiran) show promise 1

• Liver disease patients:

  • At higher risk of coagulopathy due to decreased production of coagulation factors and dysfunctional fibrinogen
  • May develop significant coagulopathy with less blood loss 1
  • Require more aggressive management and monitoring