over 40% of patients being treated with oral anticoagulation are prescribed a direct oral anticoagulants ( doacs ) according to a recent study assessing prescribing patterns 1 .
pivotal trials for the doacs have reported noninferiority or superiority of these agents to warfarin , a vitamin k antagonist ( vka ) , for multiple indications including nonvalvular atrial fibrillation ( af ) and venous thromboembolism ( vte ) 2 , 3 , 4 , 5 .
furthermore , several of these studies also demonstrated similar or lower rates of minor and major bleeding and eliminates the need for frequent laboratory monitoring of these doacs in comparison with warfarin .
despite these benefits , dabigatran , a direct thrombin inhibitor , is the only doac with an fdaapproved reversal agent idarucizumab currently on the market 6 .
currently , other doacs such as rivaroxaban , apixaban , and edoxaban , lacks an fdaapproved reversal agent , although there are currently multiple agents in the pipeline for reversing these newer anticoagulants 7 . as a result ,
the current mainstay management of factor xa inhibitorinduced bleeding is supportive care with traditional blood products such as packed red blood cells ( prbc ) , as the anticoagulant effects of rivaroxaban can be expected to last 24  h or more 8 .
fourfactor prothrombin complex concentrate ( 4fpcc ) , the only pcc formulation currently available in the united states , contains factors ii , vii , ix , and x , proteins c and s , and heparin .
this agent is currently only fdaapproved for the management of acute major bleeding or need for urgent surgery or invasive procedures in patients on vka , with dosing recommendations based on international normalized ratio ( inr ) values .
the 2012 chest antithrombotic guideline provides a level 2c recommendation for 4fpcc in the management of vkaassociated major bleeds over plasma products 9 , although the guideline supplement is published 1  year after rivaroxaban is initially approved in the united states .
we report the following case of a 69yearold caucasian male anticoagulated with rivaroxaban 20  mg orally every morning with meals for chronic nonvalvular af ( cha2ds2vasc=5 ) , admitted to the cardiothoracic intensive care unit for emergent onpump coronary artery bypass graft due to stelevated myocardial infarction and hemodynamic instability secondary to confirm thrombosis of a previously inserted left anterior descending ( lad ) artery stent .
the patient had a past medical history of chronic nonvalvular af , coronary artery disease with two coronary stents of the lad and first diagonal branch arteries , systolic heart failure , type ii diabetes mellitus , and hypertension .
he had been experiencing angina that wax and wane for the past week that intensified prompting admission to an outside facility .
he deteriorated overnight and was initiated on intravenous ( iv ) unfractionated heparin and bivalirudin , and sedated and intubated at the facility .
emergent left heart catheterization was performed and found thrombosis of the lad stent with a left ventricular enddiastolic pressure of 15  mmhg necessitating placement of a 1:1 intraaortic balloon pump placement .
overnight at the facility , bivalirudin was discontinued , and in the morning , he received rivaroxaban 20  mg once at that facility , and he was immediately transferred to our facility via the air ambulance for emergent onpump coronary artery bypass graft ( cabg ) .
on admission at 5  h estimated time prior to the scheduled emergent onpump cabg , iv heparin was continued at 1200  units / h . the patient 's calculated creatinine clearance ( crcl ) via the cockcroft 
gault equation  is 95  ml / min based on his admission serum creatinine of 0.8  mg / dl and actual weight of 77.1  kg ; actual weight was used as his ideal body weight is 77.6  kg .
urine output captured 5  h as admission is 500  ml , which is equivocal to 1.2  ml / kg / h based on his actual body weight .
relevant admission hematologic laboratory markers revealed an elevated inr and activated partial thromboplastin time ( aptt ) ( table  s1 ) .
fourfactor prothrombin complex concentrate 2500  units ( 30  units / kg ) iv at 200  units / min for one dose was administered 3  h prior to the scheduled cabg ; the dose of 30  units / kg was chosen based on the review of available literature demonstrated survival for majority of patients that have received 4fpcc dosing ranging from 25 to 40  units / kg ( table  s2 ) .
twovessel onpump cabg of the lad and first diagonal branch was performed and required ~4  h of intraoperative time . in the operating room , the patient lost a total of 650  ml of blood necessitating 2  units of both prbc and platelets , respectively . following the procedure ,
he was transferred to the cardiothoracic intensive care unit for hemodynamic optimization with fluids , vasopressors , and inotropes .
on postoperative days ( pods ) 13 , he received additional units of prbc for optimization of oxygen delivery by maintaining target hemoglobin of 10  g / dl . by pod 2 ,
the intraaortic balloon pump was weaned off , he was successfully extubated from mechanical ventilation , and was initiated on a regular enteral diet .
no significant events occurred between pods 27 and by pod 7 , and he was transferred to the cardiothoracic stepdown unit for observation .
he was scheduled for discharge on pod 8 , but due to case management issues , he was discharged by pod 9 without any complications and was prescribed for rivaroxaban 20  mg orally every morning with meals . according to the patient , he prefers to take it in the morning despite recommendation by the manufacturer to take the medication in the evening for the indication of nonvalvular af . a followup visit
1  month after discharged did not reveal any new significant event , and a chest xray obtained during the visit revealed an almost complete resolution of postoperative effusions and atelectasis .
rivaroxaban inhibits coagulation factor xa , hindering the downstream coagulation cascade that involves activation of factor ii , i , and xiii thus preventing thrombogenesis 10 , 11 , 12 . in patients with a crcl greater than 50  ml / min ,
the recommended dosing of rivaroxaban for nonvalvular af is 20  mg by mouth every evening with meals .
the drug 's reported halflives with a crcl greater than 50  ml / min 59  h in adults and 1115  h in the elderly .
approximately 66% of rivaroxaban undergoes renal elimination , and the drug has a time to peak plasma concentration of 24  h. in addition , it has a large volume of distribution at approximately 50  l and is highly protein bound to albumin between 92% and 95% making it virtually nondialyzable . several blood products like 4fpcc
have been suggested by experts as reversal agents for the doacs . despite being approved for urgent reversal of vka
, some experts believe that 4fpcc may still be beneficial when used for severe bleeding or urgent reversal with doacs as it replenishes factor ii , vii , ix , x , and proteins c and s based on published case reports and series across different patient population , although the dosing and outcomes of these publications have been conflicting , and very limited or no information was provided on potential confounders ( e.g. , inr , concurrent disease states ) for several of these cases ( table  s2 ) 13 , 14 , 15 , 16 . while bivalirudin is known to cause false elevation in inr , it is unlikely contributory to the initial inr elevation upon admission as the medication was discontinued overnight , and the serum concentration of the drug on admission is most likely negligible based on the drug 's reported halflife of 25  min with a crcl greater than 90  ml / min 17 . while there is conflicting publications regarding the utility of 4fpcc in the reversal of bleeding from rivaroxaban and other doacs , the case presented demonstrated both the efficacy and safety of 4fpcc for the migration of rivaroxabaninduced bleeding for emergent cabg .
our patient received 30  units / kg of 4fpcc , 2  units of prbc , and 2  units of platelets which differ from other cases where patients have received between 25 and 50  units / kg of 4fpcc , and between 1 and 10  units of prbc .
as there is no established standard on the dosing of 4fpcc for doacs across hospitals , the risk of administration and excessive dosing must be weighed as 4fpcc carries a black box warning for thromboembolic events .
as the cases evaluated demonstrated survival between 25 and 40  units / kg , we have chosen 30  units / kg as an approximate median value based on risk versus benefit .
furthermore , cost should also be a consideration for appropriate utilization of the drug as the average wholesale price for each vial of 1000  units is approximately $ 1400 , and most patients will require multiple vials . ultimately , more data are needed to determine the risks versus benefits of 4fpcc in the optimal dosing of 4fpcc and the management of severe bleeding from doacs .
recently , there is a proposed management algorithm for patients on doacs based on urgency , including the use of alternative reversal agent such as activated charcoal , although the algorithm lacks dosing recommendation for 4fpcc , any information in regard to the pipeline factor xa inhibitor antidote such as andexanet  alfa , and any concrete evidence supporting its use 18 .
we present the first case of 4fpcc for the alleviation of bleeding for emergent onpump cabg with the patient discharged by pod 9 with no sequelae .
while 4fpcc may play a role in the management of rivaroxabaninduced bleeding in surgical procedures , safe and effective therapies for reversing such bleeds are urgently needed as the outcomes of 4fpcc on other doacs have been conflicting .
ml : substantial contributions to the case report : identified case , reviewed literature , drafted and revised manuscript , and final approval of the version to be published ca : reviewed literature , drafted and revised manuscript ud : cardiothoracic surgeon for the case , provided expert feedback .
 key clinical messagewe presented the first case of fourfactor prothrombin complex concentrate ( 4fpcc ) for the alleviation of bleeding for emergent onpump coronary artery bypass graft ( cabg ) with the patient discharged by postoperative day ( pod ) 9 with no sequelae . 
 until direct antidotes are available , 4fpcc may play a role in the management of mitigating rivaroxabaninduced bleeding in surgical procedure . 
Introduction
Case Report
Discussion
Conclusion
Conflict of Interest
Authorship
Supporting information