Bleeding reversal of anticoagulation and antiplatelet in active bleed
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 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.
Reversal of Antiplatelet Agents
Reversal of Aspirin
Reversal of Clopidogrel
Reversal of Prasugrel
- 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.
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: [1]
- 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
- Takes time, coagulation factors that were inhibited during anticoagulation must be re-synthesized by body, and this takes time.
- IV vitamin K is faster, there can be allergic reactions, but at one day, the INR may still be elevated despite Vitamin K therapy
Profactor Concentrate (PCC)
- See discussion under Factor Xa inhibitors
IN===Fresh frozen Plaza (FFP)===
- The lowest INR you can achieve is 1.5, which is that of plasma
Recombinant Factor VIIa
Reversal of Factor Xa Inhibitors
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. [2] Small animal and rodent models may not be sufficient for assessing anticoagulation reversal, as rodents may have a different structure of Factor VII.[3] 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 [4] 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)
- 4 Component PCC contains factor 2, factor 7, factor 9, factor 10, Protein S, Protein C (Trade names are Beriplex in Europe, Kcentra in United States)
- Activated PCC: contains factor 2, activated factors 7, factor 9, factor 10
- 3 fators PCC: contains factor 2, low amounts of factor 7, factor 9, factor 10
- PCC vs FFP: Sarode showed that 4 factor Profactor concentrate (PCC) is more rapid that fresh frozen plasma (FFP) Effective hemostasis in 71% with PCC vs 68% with FFP (p=NS). IF there was a visible site of bleeding PCC was more effective than FFP (82.6% vs 50%, p=0.02)
- Despite adminisration of PCC in ICH, there is still a 42% mortality [5]
- Profilnine may reverse thrombin generation better than Beriplex
Tranexamic Acid
- There is a state of hyper - fibrinolysis in trauma ([6])
- Limited data that exists comes from orthopedic and cardiothoracic surgery
Recombinant Factor VIIa
Adexanet 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.
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