Annals of B Pod: Anti-Xa Overdose

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HISTORY OF PRESENT ILLNESS

A female in her 30s arrives to the emergency department via emergency medical services. Per report, she called to declare ingestion of an unknown amount of several medications (possibly insulin, antihypertensives, and anticoagulants) in an attempt for self-harm. She initially agreed to be transported to the hospital by ambulance, but jumped from the moving vehicle and was subsequently struck and pinned under the fuselage for 10-15 minutes. After rescue, she had an apparent head injury and was confused but protecting her airway with grossly normal vital signs. She arrives in the emergency department agitated and unable to answer questions appropriately.

Past Medical History: Autoimmune hepatitis, hyperlipidemia, hypertension, diabetes mellitus II, venous thromboembolism

Past Surgical History: Cholecystectomy, Roux-en-Y

Medications: Carvedilol, chloroquine, clonidine, colchicine, hydralazine, hydrochlorothiazide, lispro, glargine, phenergan, prednisone, nifedipine, rivaroxaban, spironolactone, venlafaxine, valsartan

Allergies: Acetaminophen, iodinated contrast media (anaphylaxis), Vancomycin and compazine (rash), Haldol and lorazepam (agitation)

Physical exam

Vitals: HR: 110, BP 157/107, RR: 20, SpO2 100% ORA, T 97.9

The patient is agitated on a backboard with C-collar in place. Her primary survey reveals an intact airway, bilateral breath sounds and a strong carotid pulse. She has a 3-centimeter posterior scalp laceration. Her pupils are equal, round, and reactive to light. She has a tachycardic rate and regular rhythm. The abdomen is non-distended and soft. The pelvis is stable. She has cool extremities but strong peripheral pulses. The back exam revealed no bony step-offs and normal rectal tone. She has a Glasgow Coma Scale (GCS) of 14 (E4 V4 M6 - 1 off for confusion).

Notable diagnostics

Point-of-care glucose (initial): 274

PT/INR: 47.4/4.9
Anti-Xa: undetectable
TEG R value: 85 minutes (normal 5-10 minutes)

Lactate: 3.8

CT HEAD
Bilateral hemorrhagic contusions, left subdural hematoma with mass effect, scattered subarachnoid hemorrhage, occipital bone fracture and venous thrombosis adjacent to fracture site.

Hospital Course

Based on the primary survey, no acute airway interventions were undertaken. The patient required analgesic dosages of ketamine for sedation to facilitate workup as she presented significantly agitated, potentially due to pain. Intravenous access was difficult and attempts at central access were undertaken at the subclavian and femoral sites. Ultimately, a femoral central venous catheter was placed with no complications. At the site of the subclavian attempt, a large hematoma formed (note related above CT finding) and pressure dressing was applied to assist with hemostasis. Preliminary read of the CT head revealed significant intracranial hemorrhage as above. Prior to consultation or intervention regarding the above injuries, the patient was found to have significant pooling secretions in her mouth with worsening hypoxia.The patient was ultimately intubated for airway protection using succinylcholine and ketamine. Following confirmation of endotracheal tube placement, the patient was evaluated by the neurosurgical service.

The patient was admitted to the neurosciences intensive care unit under the care of the trauma surgery service. Given her intracranial hemorrhages, significant attempts were made to improve coagulation including administration of IV vitamin K, 3 units of fresh frozen plasma, and administration of four-factor prothrombin complex concentrate (PCC, Kcentra). While her anti-Xa level was undetectable, hematology favored excessive consumption of rivaroxaban as the underlying cause of her coagulopathy and lack of response to the above interventions. Thus, she ultimately received reversal with Andexanet alfa with standard dosing after repeat head imaging revealed worsening subdural hematoma and bifrontal contusions with midline shift. The decision was made to proceed with decompressive hemicraniectomy immediately following andexanet alfa administration. The hemicraniectomy successfully relieved the intracranial pressure leading to midline shift and she maintained consistent, although diminished, neurologic function. She was subsequently hospitalized for two weeks undergoing management for acute severe traumatic brain injury, for which she ultimately had several residual neurocognitive deficits. She was ultimately discharged with need for ongoing rehabilitation and home healthcare.

DISCUSSION

Epidemiology and Background

Rivaroxaban, along with other direct oral anticoagulants (DOACs), has become a mainstay of treatment for pro-thrombotic conditions since 2011. [1] Unlike prior anticoagulation agents, such as heparin or warfarin, rivaroxaban is a competitive small molecule inhibitor of the Factor Xa protein, both in the circulation and in already-formed clots. [2] After its initial approval for use in ischemic stroke prevention, rivaroxaban rose meteorically in popularity to ultimately gain FDA approval for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), prophylaxis against DVTs in myriad surgical settings, and secondary prevention of major adverse cardiac events following acute coronary syndrome (ACS). [3-5] From a patient perspective, DOACs are favorable for daily dosing, oral intake, and lack of frequent clinical visits for dosing adjustments.

Unsurprisingly, the primary adverse effect of appropriate DOAC use is bleeding. Major bleeding is characterized by hemodynamic compromise, requirement for transfusion, and bleeding in physi- ologically important sites. [6] Intracranial hemorrhage of any kind is considered a critical or major bleed. In individuals without major trauma, this may present with a headache, vomiting, dizziness, depressed mental status up to coma, or focal neurological deficits. Of note, worsening mental status, stupor or coma, or progression of neurologic deficits are particularly concerning. In the case of the above patient, the presence of significant trauma to the head should immediately clue the provider into the need for head imaging, especially in the setting of a potential anticoagulant overdose. The emergency physician should also be aware of other areas of major bleeding which include intraocular hematoma, pericardial tamponade, airway bleeding, hemothorax or extremity bleeding that leads to compartment syndrome.

Evaluation and Diagnosis

Testing to diagnose DOAC overdose differs from typical tests used to evaluate heparin and warfarin usage. Unlike these drugs, excessive dosage of a DOAC such as rivaroxaban may not trigger a prolongation of the prothrombin time (PT) or the activated partial thromboplastin clotting time (aPTT) and normal results should not diminish one's concern. [7] In the case of this patient, the PT was quite prolonged which may suggest severity of disease, but does not rule in or rule out rivaroxaban overdose. The thromboelastography assay similarly will display prolonged R-time (activating clotting time), but this is non-specific. The gold-standard assay is an anti-FXa assay which directly tests Factor X inhibition. However, crucially, this assay must be calibrated to the agent of interest. [8] In this case, the patient’s anti-FXa test was calibrated for heparin and therefore resulted as normal, delaying the administration of a reversal agent.

Discussion of Evidence for Management

Initial management of DOAC overdose centers around establishing large-bore intravenous access and providing adequate resuscitation for hemodynamically unstable patients. Controlling active external bleeding with pressure and packing is essential. This does not deviate from general resuscitation principles for acute hemorrhage. One additional weapon in the armamentarium against DOAC overdose is a reversal agent. Andexanet alfa is a recombinant human factor Xa “decoy protein” that binds the DOAC but does not possess any intrinsic catalytic activity. [9] DOACs bind to Andexanet alfa in a 1:1 stoichiometric ratio, similarly to endogenous factor Xa. This is important because drug efficacy will therefore depend on each patient’s DOAC dosing. Providing an initial bolus of andexanet alfa followed by continuous infusion is most effective. [10] The dosage of both the bolus and infusion are determined based on which DOAC the patient is taking, the dosage, and time since last ingestion. Andexanet alfa was found to achieve effective hemostasis in 79% of major bleeding cases associated with factor Xa inhibitors when the DOAC is taken at standard treatment doses. [11] The primary adverse effect of DOAC reversal is venous thrombosis. Indeed, the use of Andexanet alfa was associated with approximately 20% chance of thrombotic event in the 30 days following administration, so the choice to reverse a DOAC should not be made lightly. Additionally, little to no evidence exists for management of a true factor Xa inhibitor overdose rather than major bleeding seen on routine doses. Thus, the dosing should be an open conversation with your pharmacist and hematology colleagues.

SUMMARY

Direct oral anticoagulants when taken in large quantities can cause bleeding and hemodynamic compromise. Treatment of patients who overdose on a Factor Xa Inhibitor like rivaroxaban include establishing large bore peripheral IV access, controlling active external hemorrhage and treatment with Andexanet alfa, a recombinant human factor Xa. Andexanet alfa acts as a "decoy protein" that binds the DOAC rendering it inactive.

AUTHORED BY Cody stothers, MD, pHd

Dr. Stothers is a PGY-2 in Emergency Medicine at the University of Cincinnati

EDITING BY Jazmyn Shaw, MD AND THE ANNALS OF B POD EDITORS

REFERENCES

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  5. Yuan, J. Efficacy and safety of adding rivaroxaban to the anti-platelet regimen in patients with coronary artery disease: a systematic review and meta-analysis of randomized controlled trials. BMC Pharmacol Toxicol. 2018. May 2; 19(1): 19.

  6. Schulman, S et al. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost. 2010. Jan; 8(1): 202-4.

  7. Samuelson, B.T., et al. Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: a systematic review. Chest. 2017. Jan; 151(1): 127-138.

  8. Cuker A, et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol. 2014. Sep 16; 64(11): 1128-39.

  9. Lu G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013. Apr; 19(4): 446-51.

  10. Carpenter E, et al. Andexanet alfa for reversal of factor Xa inhibitor-associated anticoagulation. Ther Adv Drug Saf. 2019. Nov 26; 10.

  11. Connolly, SJ et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016. Sep 22; 375(12): 1131-41.