Therapeutic Plasma Exchange for Apixaban Removal in the Setting of Delayed Clearance and Life-Threatening Bleeding

Introduction:

The management of bleeding associated with direct oral anticoagulants (DOACs) is challenging and associated with high risk of morbidity/mortality despite the use of various reversal agents (Gomez-Outes et al. 2021). Routine tests cannot determine the level of DOAC anticoagulation and reversal agents carry potential prothrombotic complications (Garcia & Crowther 2021). We present an unusual case of a patient requiring emergent surgery with significant post-op bleeding due to profoundly delayed apixaban elimination.

Case Description:

A 63-year-old female presented to the emergency department (ED) with a 10-day history of worsening abdominal pain, distension, nausea and constipation. Her past medical history was notable for right sided heart failure, COVID-19 pneumonia requiring intubation, tissue mitral valve replacement, and post-op atrial fibrillation for which she was prescribed apixaban 5 mg BID. Her last dose of apixaban had been the night prior to ED presentation.

In the ED, a CT of the abdomen revealed a 6 cm partially obstructing lesion involving the mid-sigmoid colon. Findings were consistent with evolving peritonitis and the patient underwent an emergent exploratory laparotomy, sigmoid resection, and end colostomy. Pre-op labs revealed WBC 12.4 x10 ⁹/L, hemoglobin (hgb) 9.2 g/dL, and platelets 318 x10 ⁹/L. Coagulation studies revealed a PT of 28 sec and INR of 2.5. The patient was given prothrombin complex concentrate (PCC) 25 units/kg and 1 mg of vitamin K prior to surgery. Postoperatively, the INR remained elevated, 2.0, and her hgb downtrended from 8.8 g/dL to 7.8 g/dL. On post-op day 1 the patient became hypotensive, with increased abdominal pain/distension, she also started bleeding from her ostomy. The INR was 2.4 and her hgb dropped to 6.0 g/dL. Red blood cells were given along with FFP, vitamin K and a 2 ^nd dose of PCC. The patient continued to decline, was transferred to the ICU where she was intubated and placed on CRRT. Hematology was consulted for the persistently prolonged PT/INR in the setting of bleeding despite multiple interventions to correct the INR.

The patient's last dose of apixaban was ~48 h prior to ICU admission. A rapid heparin anti-Xa assay was performed and upon comparison with an in-house nomogram the result, 1.78 IU/mL, correlated to an apixaban dose between 180-200 ng/ml (average peak levels 2-4 h after administration are 171 ng/mL). This result was confirmed the following day by an apixaban anti-Xa assay, 190 ng/mL. A repeat test performed 11 h later showed a minimal decrease in apixaban indicating impaired clearance.

Therapeutic plasma exchange (TPE) was considered for rapid removal of apixaban. We performed a 1.0 plasma volume exchange, using plasma as the replacement fluid, to remove apixaban. Pre and post TPE drug levels were 172 and 108 ng/mL, respectively. Due to an elevated apixaban level the next day, a second TPE was performed which dropped the level to 87 ng/mL. The patient began to improve clinically, with hgb stabilization ~10 g/dL. She was extubated and transferred to a medical floor for further management. Apixaban levels were still measurable, 16 ng/mL, on post op day 8, 11 days after her last dose.

Discussion:

Apixaban is a highly protein-bound drug (~90%) that is rapidly absorbed in the small intestine with a large Vd (21 L) and a t1/2 of ~12 h. Elimination primarily occurs through the fecal route (Byon et al. 2019). The factors impairing the elimination of the drug in this patient were the following: 1. Pre-op constipation resulting in 10 days without a bowel movement; 2. Minimal bowel function post-op; and 3. Renal failure requiring CRRT after admission to the ICU.

This case illustrates the profound effect intestinal obstruction/dysfunction can have on apixaban clearance. It also highlights the importance of laboratory test interpretation when managing coagulopathic patients. TPE is an effective way to remove drugs with high protein binding affinity (Mahmoud et al. 2021). TPE significantly reduced apixaban levels in our patient allowing for hemostasis and clinical improvement. To our knowledge, there are only two case reports regarding the effect of TPE on DOACs, one for apixaban, the other rivaroxaban (Hodulik et al. 2019).

Conclusion:

TPE can be considered as an option for rapid clearance of apixaban, or other highly protein bound anti-Xa inhibitors, in the setting of delayed elimination or when specific reversal agents are not safe/available.