A 68 year old female is in the ICU following vascular surgery. She was given 14,000 units of IV unfractionated heparin approximately 60 minutes ago for anticoagulation. During observation, she shows signs of bleeding at the surgical site with an elevated aPTT and the team decides to reverse the anticoagulation.
Past medical history:
Type 2 diabetes mellitus: Metformin 1000mg BID, Ozempic 2mg SQ weekly, Jardiance 25mg daily
Peripheral neuropathy: Lyrica 150mg BID
Back spasms: Cyclobenzaprine 10mg TID PRN
Hypertension: Amlodipine 5mg daily, Losartan 25mg daily
Hyperlipidemia: Rosuvastatin 40mg nightly, Ezetimibe 10mg daily
Pertinent lab values
Temp: 98.9°F
BP: 139/78
HR: 85 bpm
K+: 4.6 mEq/L
WBC: 8K cells/mm3
aPTT: > 120 seconds (60-100 seconds)
Activated clotting time (ACT): > 600 seconds (300-550 seconds)
Which of the following would be appropriate to reverse the anticoagulant effects of unfractionated heparin?
A. Andexanet alpha
B. Protamine sulfate
C. Vitamin K
D. 4-factor prothrombin complex concentrate
E. Idarucizumab
Answer with rationale:
Anticoagulation is essential in preventing and treating thromboembolic events, however it also increases the risk of bleeding, especially in surgical or emergency situations. Reversal of anticoagulation is often required if patients experience significant bleeding, require urgent and unexpected surgery, or have supratherapeutic anticoagulation levels. Important factors to keep in mind when choosing and dosing reversal agents include the timing of the last anticoagulant dose and and the reason anticoagulation was indicated.
Unfractionated heparin (UFH) is commonly used IV for DVT and PE treatment, cardiac surgeries, acute coronary syndromes, and vascular surgeries. It acts by binding to Antithrombin III (ATIII), which then binds to and inhibits thrombin and clotting factor Xa. This prevents fibrinogen from converting to fibrin, inhibiting clot formation. Its anticoagulant effect can be measured with activated partial thromboplastin time (aPTT), giving an idea of how to monitor and adjust dosing. In some centers, factor Xa monitoring is done instead of aPTT as it may have a more direct and reliable result.
Answer A is incorrect: Andexanet alpha (Andexxa) is used for the reversal of direct oral anticoagulants (DOACs) like apixaban and rivaroxaban. It acts like a decoy of factor Xa, binding to DOACs and inactivating them, so it would have no effect on heparin reversal.
Answer B is correct: Protamine sulfate is the preferred agent for UFH reversal, and it is given intravenously. It neutralizes the activity of heparin by forming a stable salt. The regimen for protamine depends on the route, amount, and timing of heparin received by the patient. If heparin was given subcutaneously for prophylaxis, 1mg of protamine should be given per 100 units of heparin received in the last 8 hours. If the patient was receiving IV heparin, 1mg of protamine should be given per 100 units of heparin received in the last 2-3 hours (per institutional policy).
It is important to note that protamine actually acts as an anticoagulant if too high of a concentration exists and there is not enough heparin to bind to, so there is a maximum single dose of 50mg. Common adverse reactions to protamine include hypotension and bradycardia, which are more likely at higher rates of administration, so it is typically capped at 5mg/minute (per institutional policy).
Answer C is incorrect: Vitamin K is a common reversal agent for warfarin, as warfarin’s mechanism of action is to inhibit vitamin K, which disrupts the synthesis of several clotting factors. Dosing of vitamin K is based on the patient’s INR and severity of bleeding.
Answer D is incorrect: 4-PCC (4-factor prothrombin complex concentrate) is another option for warfarin and possibly DOAC reversal. It works by replenishing several clotting factors that can be inhibited by these anticoagulants, but does not have a therapeutic reversal effect on heparin.
Answer E is incorrect: Idarucizumab is a monoclonal antibody that binds directly to dabigatran to reverse its anticoagulant effects. The brand names for dabigatran (Pradaxa) and Idarucizumab (PRAXBIND) make it a little easier to remember their association.
Brand/generics Covered:
Andexanet alpha (Andexxa), Protamine (no active brand name), Idarucizumab (PRAXBIND), Dabigatran (Pradaxa), Apixaban (Eliquis), Rivaroxaban (Xarelto), Warfarin (Coumadin, Jantoven)
Naplex Content Domains Covered
2.A.1,2 - Drug names and indications
3.C.2 - Appropriateness of Therapy