An Older Woman with Acute Calculus Cholecystitis

A 64-year-old woman is admitted with acute calculus cholecystitis. Over the last 48 hours, she has had steadily increasing pain in the right upper quadrant, accompanied by nausea and vomiting. She has also become febrile in the past 24 hours. 

The patient reports a similar, but less severe, episode about 6 months prior. An ultrasound performed in the emergency room at that time was positive for gallbladder calcluli.

History

Her personal medical history is very significant for adult onset diabetes mellitus of 10-years duration, which is controlled by metformin and sulfonylurea. She also has a 2-year history of rate-controlled atrial fibrillation. This is treated with metroprolol and she is also on anticoagulation prophylaxis with rivaroxaban. She is very compliant with her stroke prophylaxis such that she has continued to take her medications as recently as the evening prior.

Laboratory Tests

Laboratory evaluation reveals a leukocytosis with shift. Her random blood glucose is 169 mg/dL, blood urea nitrogen level of 24 mg/dL, creatinine level of 1.8 mg/dL (creatinine clearance estimated 40 cc/min) and bilirubin at 1.5 mg/dL. Serum amylase is 298 u/dL. 

Both surgery and gastroenterology have been consulted; an imminent procedure is possible, however there are questions about her anticoagulation status.

Which of the following is the most accurate statement about the presented patient?

A. The prothrombin time is the most readily available test to detect the presence of rivaroxaban activity.
B. She should receive 4 u of fresh frozen plasma to reverse her anticoangulant effect.
C. She should receive a dose of activated VII to reverse her anticoagulant effect.
D. Surgery can safely be performed, even emergently, since the direct oral anticoagulants have short half-lives and potential hemorrhage is not an issue.

(Answer and discussion on next page)

Correct Answer: A

This case exemplifies the evolving medicine of the “new” direct oral anticoagulants (DOACs). The most often used drugs are dabigatran, a direct thrombin inhibitor, and rivaroxaban, an oral Xa inhibitor. 

The perceived advantages include their oral route, pharmacology that results in rapid onset of action (and offset as well, assuming normal renal clearance), and the lack of need for monitoring. However, problems accruing to these agents include a lack of methodology to ascertain presence and degree of anticoagulant effect and, most importantly, the lack of a true and proven antidote. 

This Case

The presented case highlights several of these issues: 

• How much anticoagulant effect is present in a patient with waxing and waning renal function who needs invasive procedures that would predispose her to hemorrhage?

• How to reverse or at least ameliorate the anticoagulant effect?

Regarding “measuring” anticoagulant effect, data is now accruing that at least allows us to know whether anticoagulant effect is present, and to a lesser degree how much effect is present.¹ The referenced review considered prompt test availability and linearity of test response to dosage and standardization. 

For dabigatran, candidate-appropriate assays are dilute-thrombin time, which seems to correlate with dosage effect, and a routine partial thrombin time or PTT to ascertain a more simple yes or no answer regarding dabigatran effect being present.^1,2 For rivaroxaban, the prothrombin time (PT) serves both purposes—yes or no regarding the rivaroxaban effect and to a substantial degree, how much.² Thus, Answer A is correct.

Differential Diagnosis

Answer D is not correct because of the known pharmacology of these agents and their lack of an antidote at this time. Specifically, rivaroxaban is essentially entirely cleared by glomerular filtration and with normal renal function its T½ approximates 5 to 9 hours.¹ However, as GFR decreases, the T½ prolongs and a significant degree of acute renal failure is present in our patient. Thus, it cannot be assumed the T½ is short in our patient. In fact, significant anticoagulant effect may be present for a prolonged period and there is indeed a potential risk for hemorrhage with surgery.

Answers B and C addresses the issue of antidotes for DOACs. At this time, there simply is no proven effective antidote. A lot of conference room anecdote messaging has generated opinions regarding procoagulant maneuvers, such as prothrombin complex concentrates and the ubiquitously mentioned (but rarely with vigorously documented proven effect) activated VIIa. The most clinically promising agents seems to be prothrombin complex concentrates (Note: A new quadrivalent prothrombin complex concentrate has recently received FDA approval for coumadin-related hemorrhage) and theoretically, a fragment antigen-binding that can bind and block dabigatran^3-5 with a biochemistry and theory similar to digoxin binding agents. Time and data will determine which come to fruition. For now, there are no antidotes for DOACs.

Outcome of the Case

The patient was vigorously hydrated and by the next morning, her creatinine was 1.0 mg/dL with a creatinine clearance estimate >60 cc/min. An initial PT was 1.9 times baseline and by the following morning was normal. She underwent a successful endoscopic retrograde cholangiopancreatography with ampullotomy on hospital day 2. An elective cholecystectomy is planned.

Take-Home Message

Direct oral anticoagulants, such as dabigatran and rivaroxaban, are increasingly used as anticoagulants. Several trials have demonstrated that they are safe and effective when administered without dose adjustments. However, there are instances where such assumptions are not valid and where some sort of evaluation regarding presence and degree of anticoagulant effect is helpful—such as preoperatively (especially emergently), in the setting of waxing/waning renal function where clearance may be delayed, and adverse events, such as trauma or spontaneous bleeding. 

For dabigatran, the PTT and thrombin time, but not the PT, have been useful. For rivaroxaban, the PT and factor xa assay have been found useful. Reversal therapy is problematic and remains in study.

Ronald Rubin, MD, is a professor of medicine at Temple University School of Medicine and chief of clinical hematology in the department of medicine at Temple University Hospital, both in Philadelphia.

References:

1.Tripodi A. The laboratory and the direct oral anticoagulants. Blood. 2013;121(20): 4032-4035.

2.Eerenberg ES, Kamphuisen PW, Sipkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized placebo-controlled crossover study in healthy subjects. Circulation. 2011;124(14):1573-1579.

3.Baglin T, Hillarp A, Tripodi A, et al. Measuring oral direct inhibitors (ODIs) of thrombin and factor Xa: a recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2013;
11:756-760. 

4.Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;
121(181):3554-3562.

5.Millar CM, Lane DA. Blocking direct inhibitor bleeding. Blood. 2013;121(18):3543-3544. An excellent review addressing issues discussed in this WTTH:Hunt BJ. Bleeding and coagulopathies in critical care. N Eng J Med. 2014;370(9):847-859.