Intracerebral Hemorrhage Due to Anticoagulant Therapy

Patients taking anticoagulants have larger baseline intracerebral hemorrhage volume, greater early hemorrhage expansion, and increased morbidity and mortality compared to those not on anticoagulants. While there is little formal data proving that prompt reversal of anticoagulation improves outcome, most experts agree that aggressive, rapid reversal is an important intervention likely to limit brain injury in this scenario. Reversal protocols are largely based on expert opinion as opposed to clinical trial data, and institutions often have specific internal reversal protocols based on local expertise and resource availability. The recommendations presented here represent one of many reasonable approaches.

A.

In the case of unfractionated heparin, protamine is the typical reversal agent. Protamine 1 mg neutralizes about 100 units of unfractionated heparin, with a maximal dose of 50 mg. Because intravenous heparin has a short plasma half-life, the amount administered within the preceding 2–3 hours may reasonably represent the total active dose that needs to be reversed. For example, if a heparin infusion has been running at 1000 units/hour for the past 3 hours, reversal of 3000 units would be appropriate, which requires 30 mg of protamine. A single dose of protamine is usually sufficient because of the short half-life of intravenous (IV) heparin, but activated partial thromboplastin time (aPTT) should be checked after protamine administration to ensure adequate reversal.
B.

For patients receiving prophylactic doses of subcutaneous heparin, reversal is typically not warranted. aPTT levels should be checked, and if elevated, protamine can be dosed accordingly. If needed, the exact dose of protamine is unclear in the context of subcutaneous heparin, but the longer half-life warrants surveillance of aPTT and redosing of protamine as needed.
C.

For low-molecular-weight heparin, protamine achieves partial reversal (about 60%–80% of anti-Xa activity). Protamine dosing depends on the timing and dose of low-molecular-weight heparin. Recombinant factor VIIa can be considered in patients with refractory life-threatening bleeding.
D.

The need for reversal of direct oral anticoagulants (DOAC) depends on the time from last dose. Some conservative protocols advocate for reversal if the last dose was within 48 hours, but given the relatively short half-life of these medications, reversal for use within 24 hours is probably most reasonable. Betrixaban has a longer half-life, so late reversal might be considered with this agent. If the time of last DOAC dose in unknown, it is appropriate to proceed with reversal. If last dose was within 2 hours, activated charcoal can be considered to reduce absorption of any remaining unabsorbed drug.
E.

Thrombin time is very sensitive to dabigatran, so if the thrombin time is normal, reversal is not needed. However, rapidly obtaining this measurement is difficult at many centers, and treatment should not be delayed to await thrombin time results. Idarucizumab is a humanized monoclonal antibody that uniquely binds dabigatran given as two separate 2.5 mg IV doses, separated by no more than 15 minutes. If idarucizimab is not available, prothrombin complex concentrate (PCC) can be considered (50 units/kg, maximum dose 5000 units). Alternatively, hemodialysis can also be considered to remove circulating dabigatran, particularly if there is renal insufficiency. Consultation with pharmacy and hematology is appropriate.
F.

Andexanet alfa is a reversal agent specific to factor Xa inhibitors. Dosing depends on timing and dose of DOAC. If andexanet is not available, a dose of 50 units/kg of PCC should be administered, with a maximum of 5000 units. Factor Xa inhibitors are not readily dialyzable.
G.

For warfarin related intracerebral hemorrhage, 10 mg of IV vitamin K should be administered immediately, but this does not rapidly correct the coagulopathy and normalize the international normalized ratio (INR). It is critical, then, to give 4-factor PCC for rapid warfarin reversal. The PCC dose should be selected based on INR. Typically, no reversal is needed if the INR is < 1.4. In the case of mildly elevated INR (1.4–1.9), reversal can be considered depending on the severity of bleeding. If PCC is unavailable, fresh frozen plasma (FFP) can be considered, but slower administration time and the risk of volume overload make this less desirable. The preferred initial dose of FFP is 15mL/kg or 4 units. Rechecking the INR after reversal is important to ensure the coagulopathy has been corrected.