Hangil Lee, MD Resident Physician, Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA
Introduction
Reversal of anticoagulation is one of the most critical medical managements a neurosurgeon can provide. Under-reversal can result in devastating expansion of hematomas and subsequent death or permanent disability. Over-reversal can result in hyper-coagulable state causing occlusion of the coronary, pulmonary, and peripheral vasculatures, also resulting in death or permanent disability. With the correct reversal regiment, patients have improved odds of stabilized hemorrhages, safer operations when indicated, and discharge to either rehabilitation or home.
Indications
Indication for reversal is clear: if there is blood in the brain, reverse the agent. Regardless of the etiology – stroke, traumatic subdural, aneurysmal rupture, or hemorrhage of tumor – it is prudent to reverse the anticoagulant for hemorrhage stabilization. One additional indication: for TBI patients with altered mental status, reverse if the patient is supratherapeutic (e.g. INR of 14) even if there is no hemorrhage on cranial imaging. Reversal to therapeutic or subtherapeutic levels temporarily is reasonable while the brain parenchyma remains friable from the recent trauma.
Reversal
In most scenarios, reversal is prescriptive (Table). Some anticoagulants have multiple reversal options. Regarding choice of “aggressiveness” of reversal: one should address the question of operative candidacy. Although quality randomized control evidence for pre-operative reversal is lacking, a study from the Cleveland Clinic showed that restarting anticoagulation within 48 hours of intra-axial surgery increased the risk of hemorrhage expansion (odds ratio 8.9)1. One can infer that pre-operative patients face similarly increased risks as compared to non-operative patients. Hence, for the operative patients the more “aggressive” reversal may be warranted.
Antiplatelets
The two antiplatelet agents are ddAVP, which increases the concentration of von-Willebrand Factors and Factor VIII, and platelet infusion. While ddAVP is relatively benign, infusion of platelets, a blood product, can have a myriad of complications, e.g. platelet infusion has a significant risk of volume overload, especially in patients with cardiopulmonary comorbidities.
One example that has been commonly adopted is to not reverse when aspirin (81 mg) is given alone in a non-operative patient. In all other scenarios, whether the patient is on any other antiplatelet agent(s) (i.e. clopidogrel) or is an operative candidate, reversal with both ddAVP and platelets is warranted. The specific quantity of platelets varies across institutions, typically between 3 and 6 units. Depending on the patient’s hemorrhage pattern and comorbidities, the specific quantity of platelets can be determined after discussion with the multi-disciplinary team involved.
Direct Oral Anticoagulants (DOACs)
The second class of agents are the Direct Oral Anticoagulants (DOAC)s. These directly inhibit factor X. To reverse these, one can replenish the inhibited factor with Prothrombin Complex Concentrates (PCC) or by using a decoy factor X protein called Andexanet alfa.
The benefit of Andexanet is that it works rapidly (5 minutes) and virtually fully reverses the anticoagulative effects of DOACs (Figure). However, its limitations are considerable: It is
Table: Anticoagulants and their reversal agents
expensive (approximately $25,000) and only therapeutic for the duration of the infusion (2 hours). Once the infusion is completed, the reversal ends immediately; anticoagulation is again in effect. To prevent this if Andexanet is considered, an additional longer-lasting agent such as PCC should be given as well to prevent rebound anticoagulation. Because of these limitations, Andexanet is typically reserved for operative patients when available.
PCC is a good alternative: it has an onset of 30 minutes and is more affordable. PCC also has a shorter half-life than DOACs (6-8 hrs vs. 12 hrs) and will need redosing.
Warfarin
Warfarin works by blocking vitamin K epoxide reductase, which decreases the activation of factors II, VII, IX, and X. Like DOAC reversal, replenishment of the inhibited factors with PCC is a good strategy with appropriate re-dosing (half-lives: 6-8 hrs (PCC) vs. 40 hrs (warfarin)). Despite being more affordable than Andexanet, PCC is also relatively costly and is not widely available in LMICs. An alternative is fresh frozen plasma (FFP). Like platelets, FFP may cause transfusion-related reactions and volume-related complications. If both PCC and FFP are available, PCC is superior in most ways except for cost. Depending on the specific institution and its payment model, benefits and disadvantages should be weighed prior to reversal selection.
Restarting Anticoagulation
Once the hemorrhage has been stabilized and the patient begins to recover from the bleeding event, anticoagulation must be restarted for the original indication if determined to be necessary. If the indication was soft, the risks and benefits of restarting should be thoroughly discussed with the patient and/or family. If the indication is for lower extremity deep venous thrombosis (DVT), an inferior vena cava (IVC) filter should be considered to prevent embolisms while further delaying anticoagulation initiation to optimize the intracranial hemorrhage stabilization.
There are unfortunately no good trials to guide safe restart timing of anticoagulation, although a study from the Cleveland Clinic does shed light on when we should not restart anticoagulation, which is within 48 hours of intra-axial surgery1. Beyond the 48 hours, there is a theoretical benefit
Figure: Andexanet alfa and its therapeutic reversal limited to infusion duration
in waiting 4-5 half-lives for full excretion of previously given anticoagulation agents from pre- bleeding to prevent patients from becoming supra-therapeutic. Hence, a good rule of thumb, as long as there are no acute life-threatening indications for anticoagulation, is to wait 2-3 days for DOACs and 5 days for warfarin.
Pre-operatively, the same duration of holding applies for very similar reasons. We should wait for the anticoagulant to be completely excreted prior to conducting elective intra-cranial work. If time off anticoagulation needs to be limited, bridging with heparin should be considered for its short half-life (30 mins to 2 hours) and ease of reversal with protamine.
DVT Prophylaxis
One must emphasize that low dose subcutaneous heparin for DVT prophylaxis in trauma patients is different from full anticoagulation. Once the intracranial bleed is determined to be stable (CT scan at 24 hours), one should begin pharmacological DVT prophylaxis as trauma dramatically increases the rate of DVTs. Avoid lovenox for this purpose since it is not as easily reversed as heparin in the rare occasion of hematoma expansion after initiation of DVT prophylaxis.
In summary, reversal of anticoagulation can be both intimidating and uninspiring to neurosurgeons. Avoiding under- and over-reversal can improve outcomes and make surgery dramatically safer when indicated for these vulnerable patient populations.
Reference
1. Davison MA, Patel AA, Lilly DT, et al. Risk assessment of early therapeutic anticoagulation following cranial surgery: an institutional case series. J Neurosurg. 2024;141(4):1138-1146. doi:10.3171/2024.2.JNS24146
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