Bleeding reversal of anticoagulation and antiplatelet in active bleed

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Reversal of Anticoagulation and Antiplatelet in Active Bleed

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Overview

Bleeding in patients on antiplatelet or anticoagulation agents often necessitates reversal of the active agent. The risk of ongoing bleeding must be weighed against the risk of precipitating thrombosis in a patient who is anticoagulated. Protamine is indicated for the treatment of severe bleeding among patients on heparin. In case of bleeding among patients on vitamin K antagonists, oral or intravenous vitamin K and fresh frozen plasma have been used for anticoagulation reversal at the expense of several limitations including time for vitamin K and the need for cross matching and risk of volume overload for fresh frozen plasma. 4 factor prothrombin complex concentrate (PCC) is indicated for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist therapy in adult patients with acute major bleeding.[1] As for the new oral anticoagulation therapy agents, there are no available antidotes so far and the management for severe bleeding among patients on these medications is problematic. The evidence for the use of PCC in case of severe bleeding among patients on oral anticoagulation therapy is not robust.[2]

Reversal of Antiplatelet Agents

Reversal of Aspirin

Reversal of Clopidogrel

Reversal of Prasugrel

  • The reversal of the platelet inhibition can not be overcome except with platelet transfusion. Platelets can be administered 2 hours after a maintenance dose, and 4 hours after a loading dose. If platelets are administered earlier, the free drug will bind to the platelets and inhibit them.
  • Desmopressin can be considered with platelet transfusion.[3]

Abciximab

  • Given that this drug binds more avidly to platelets, new platelets can be infused to reduce bleeding.

Tirofiban

  • Given that this drug binds less avidly to platelets than abciximab, a transfusion of new platelets may not be effective in reducing bleeding.

Eptifibatide

  • Given that this drug binds less avidly to platelets than abciximab, a transfusion of new platelets may not be effective in reducing bleeding.

Reversal of Anticogulants

General Measures

The following are general measures to reverse anticoagulation: [4]

  • Stop drug
  • Treat bleeding lesion (mechanical compression, cauterization, coil embolization etc.)
  • Administer antidote
  • Test integrity of coagulation system, however, risk of bleeding may not parallel levels of assays
  • Use non-specific blood thickeners
  • Transfuse to replace deficient factors
  • Consider dialysis

Reversal of Warfarin

Vitamin K

  • The reversal of vitamin K antagonist with vitamin K is a time dependent process because it relies on the vitamin K dependent re-synthesis of the coagulation factors 2, 7, 9 and 10 that were inhibited during anticoagulation.
  • IV vitamin K is faster than the oral form; however, there can be allergic reactions associated with the IV administration. But at one day, the INR may still be elevated despite IV vitamin K therapy.

Profactor Concentrate (PCC)

  • According to the 2011 British guidelines on oral anticoagulation with warfarin, the administration of 4 Factor PCC and IV vitamin K is recommended to reverse warfarin among subjects with major bleed, emergency surgery and high suspicion of intracebral hematoma following head trauma.[5]
  • The 2012 American College of Chest Physicians Evidence-Based Clinical Practice Guideline recommends the administration of Factor 4 PCC in cases of major bleeding among patients on vitamin K anatagonist, and it advises for the concomitant administration of vitamin K along with it.[6]
  • The 2013 updated European guideline recommends the use of PCC among trauma patients after assessing the urgency of reversal of vitamin K antagonist versus the accompanied risk of increased risk of PCC associated thrombosis.[7]
  • A randomized phase IIIb study on the use of 4 factor PCC versus plasma for urgent vitamin K antagonist reversal among patients with acute major bleeding revealed that the administration of PCC was not inferior to plasma in decreasing the INR and increasing factor concentrations. Sarode demonstrated that 4 factor PCC is more rapid that fresh frozen plasma (FFP) with a effective hemostasis in 71% with PCC vs 68% with FFP (p=NS). In case of a visible site of bleeding, PCC was more effective than FFP (82.6% vs 50%, p=0.02).[8]

Fresh Frozen Plaza (FFP)

  • Reversal of anticoagulation with FFP is time dependent due to the need of cross matching before the administration. In addition, the administration of FFP is being associated with an increased risk of fluid overload particularly among patients with heart or kidney diseases.[1]
  • The lowest INR you can achieve is 1.5, which is that of plasma.

Recombinant Factor VIIa

Reversal of Factor Xa Inhibitors

  • New oral anticoagulation (NOAC) therapy agents are characterized by a short half life and a better bleeding profile than vitamin K antagonist. However, there are no antidotes for NOAC and the management for severe bleeding among patients on these medications is problematic. In case of non life threatening bleeding associated with factor Xa inhibitors, the management should be focused on the following:
  • In case of life threatening bleeding, the management should include the similar previously noted measures. The administration of PCC or activated PCC should be considered in severe bleeding when urgent rapid reversal of anticoagulation is needed; however, there is not enough evidence to support its use.[2]
  • For drug development, a pig model of liver trauma/injury may be optimal to assess agents that reverse Factor Xa inhibitors. In particular, pigs will die if you do not rapidly reverse this. [9] Small animal and rodent models may not be sufficient for assessing anticoagulation reversal, as rodents may have a different structure of Factor VII.[10] Reversal of coagulation parameters with PCC may not predict bleeding. INR, PT, and PTT may not reflect thrombin generation to assess reversal. You should assess thrombin generation to assess reversal of Factor Xa inhibition [11] The site of bleeding with attendant variations in factor levels, may affect mechanism of action of drugs and their reversal. In patients with ICH, reversal may be "too little too late". ICH and retroperitoneal bleeds are less common with Factor Xa inhibitors compared with warfarin. GI bleeding is more common with Factor Xa inhibitors. There is active drug in the gut of these patients. Bleeding into a closed space requires reversal, trauma bleeding requires reversal.

Profactor Concentrate (PCC)

  • As previously mentioned, there are several types of PCC: activared PCC, 4 factor PCC and 4 factor PCC (check reversal of warfarin above for more details).
  • The administration of PCC or activated PCC should be considered in severe bleeding when urgent rapid reversal of anticoagulation is needed; however, there is not enough evidence to support its use.[2] PCC is not FDA approved for the reversal of bleed among patients on factor Xa inhibitors.

Tranexamic Acid

  • There is a state of hyper - fibrinolysis in trauma ([13])
  • Limited data that exists comes from orthopedic and cardiothoracic surgery

Recombinant Factor VIIa

  • Only partially effective
  • This drug will reverse the INR, but will not restore thrombin generation

Andexanet Alfa A Factor Xa Inhibitor Reversal Agent

  • Investigational, in phase III clinical trials
  • A decoy of Factorx Xa
  • Works against Enoxaparin, Apixaban, Rivaroxaban, Edoxaban, and Betrixaban
  • Factor Xa binding site mutated to deactivate proteolytic (bleeding) activity, but binds Factor Xa inhibitors
  • Sequesters the anticoagulant
  • Apixaban 5 mg PO bid administered for 5 days, reversed by bolus of antidote in 2 minutes. An infusion continues to sequester drug. Once you turn off infusion, anticoagulation resumes. Plasma concentration of these drugs increases as it seeps in from the tissue during the process of sequestration. This antidote binds drug that is mobilized as well. Corrects thrombin generation. Corrects clotting time.

Aripazine or PER-977

  • A small 512 Dalton investigational molecule developed by Perosphere
  • Reverses Factor Xa and IIa as well as unfractionated heparin, enoxaparin and fondaparinux
  • Works by hydrogen binding, not covalent binding
  • Works in rat tail and liver laceration models
  • Phase 1 completed to assess safety and tolerability
  • It is a highly charged molecule, may interfere with assays
  • PT, thromboelastography and whole blood clotting time reduced by 300 mg dose
  • Dose dependent increase in the diameter of fibrin strands with the antidote

Reversal of Dabigatran

In case of non life threatening bleeding associated with direct thrombin inhibitors, the management should be focused on the following:

In case of life threatening bleeding, the management should include the similar previously noted measures. The administration of PCC or activated PCC should be considered in severe bleeding when urgent rapid reversal of anticoagulation is needed; however, there is not enough evidence to support its use.[2]

Idarucizumab a Dabigatran Reversal Molecule

  • Investigational Fab
  • Smaller than albumin, bigger than thrombin in molecular size
  • No off target toxicity expected, no activation of coagulation expected, no complement activation expected
  • Sucks dabigatran off its other binding sites
  • Studied in healthy human volunteers as a 5 minute infusion
  • Two compartment model, initial 45 minute half life, terminal 4.5 to 9 hour half life
  • Renal excretion
  • 4 grams completely eliminates all Dabigatran immediately
  • No evidence of prothrombotic effect in healthy volunteers
  • 1% rate of immunogenicity in healthy volunteers

References

  1. 1.0 1.1 1.2 Quinlan DJ, Eikelboom JW, Weitz JI (2013). "Four-factor prothrombin complex concentrate for urgent reversal of vitamin K antagonists in patients with major bleeding.". Circulation. 128 (11): 1179–81. PMID 23935012. doi:10.1161/CIRCULATIONAHA.113.005107. 
  2. 2.0 2.1 2.2 2.3 Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J; et al. (2013). "EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary.". Eur Heart J. 34 (27): 2094–106. PMID 23625209. doi:10.1093/eurheartj/eht134. 
  3. 3.0 3.1 3.2 Levi MM, Eerenberg E, Löwenberg E, Kamphuisen PW (2010). "Bleeding in patients using new anticoagulants or antiplatelet agents: risk factors and management.". Neth J Med. 68 (2): 68–76. PMID 20167958. 
  4. Crowther Blood 2008
  5. Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C; et al. (2011). "Guidelines on oral anticoagulation with warfarin - fourth edition.". Br J Haematol. 154 (3): 311–24. PMID 21671894. doi:10.1111/j.1365-2141.2011.08753.x. 
  6. Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ; et al. (2012). "Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.". Chest. 141 (2 Suppl): e152S–84S. PMC 3278055Freely accessible. PMID 22315259. doi:10.1378/chest.11-2295. 
  7. Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernández-Mondéjar E; et al. (2013). "Management of bleeding and coagulopathy following major trauma: an updated European guideline.". Crit Care. 17 (2): R76. PMID 23601765. doi:10.1186/cc12685. 
  8. Sarode R, Milling TJ, Refaai MA, Mangione A, Schneider A, Durn BL; et al. (2013). "Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study.". Circulation. 128 (11): 1234–43. PMID 23935011. doi:10.1161/CIRCULATIONAHA.113.002283. 
  9. FDA Think Tank Meeting, April 22,2014
  10. FDA Think Tank Meeting, April 22,2014
  11. FDA Think Tank Meeting, April 22,2014
  12. Dowlatshahi
  13. CRASH 2 study, lancet 2010

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