,

SUBMITTED:

November 2021

Accepted:

June 2022

F. Jongbloed (1,5), K. de Leur (2), C. Heetman (3), M. de Maat (6), E-J. Wils (4,7)
Departments of 1 Internal Medicine, 2 Laboratory Medicine, 3 Pharmacology and 4 Intensive Care, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands Departments of 5 Internal Medicine, 6 Haematology, and 7 Intensive Care, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands

Correspondence:

f.jongbloed@erasmusmc.nl
Case Report

An 85-year old patient with severe ongoing bleeding

Keywords:

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Abstract
In this case report, we describe an 85-year-old female patient who presented with a rare but important problem of anticoagulant rebound complicating dabigatran use. Despite multiple attempts to correct the bleeding, it continued and the coagulation times remained prolonged. Important risk factors for high dabigatran concentrations and prolonged coagulation are renal insufficiency, drug-drug interactions and older age. Treatment of dabigatran-related bleeding with idarucizumab may be complicated by a rebound effect presenting as the reappearance of dabigatran after an initial response. The risk of anticoagulation rebound is higher with higher initial dabigatran levels and is associated with the severity of renal insufficiency. The rebound is best monitored by the diluted thrombin time and may be treated with repeated doses of idarucizumab. In case of persisting bleeding and high dabigatran levels, renal replacement therapy is an acceptable therapeutic option.

Case
An 85-year-old female presented to the emergency department with pain in her right shoulder and confusion. Her medical history included chronic kidney disease (estimated glomerular filtration rate using CKD-EPI: 44 ml/min/1.73 m2), heart failure (moderate left ventricular function), and atrial fibrillation (CHAD-VASC score of 7) which had been treated for four years with amiodarone and dabigatran 110 mg twice daily, a dosage adjusted to the pre-existing decreased renal function (table 1). A week previously, triamcinolone was injected in her right shoulder because of subacromial syndrome. On arrival, her vital parameters were: temperature 36.7 °C, atrial fibrillation (89/min), blood pressure 106/59 mmHg, respiratory rate 18/min and an O2 saturation of 95% on room air. She showed a mildly disoriented mental state, diffuse abdominal pain and a swollen and painful right shoulder. Laboratory analyses (table 2) showed acute kidney failure and high inflammatory parameters.

A diagnostic puncture of the shoulder evacuated blood without crystals. Blood and joint fluid cultures were obtained and antibiotic therapy was initiated (cefuroxime 1500 mg twice daily, gentamycin 7 mg/kg once). Dabigatran was replaced by therapeutic low-molecular-weight heparin. Because of ongoing sepsis, surgery of the right shoulder was performed with evacuation of a haematoma. The haemoglobin levels dropped and the activated partial thromboplastin time (aPTT) and prothrombin time (PT) were prolonged. Despite administration of tranexamic acid, protamine and vitamin K, oozing continued and the coagulation times remained prolonged. Repeated administration of idarucizumab (5 g, 5 g and 2.5 g, respectively) only transiently corrected the bleeding and coagulation tests (figure 1), indicative of dabigatran overdosing with a rebound effect after idarucizumab administration.

Discussion
Direct oral anticoagulants (DOACs) such as dabigatran are increasingly prescribed for atrial fibrillation because of their well-documented efficacy and safety profile, without the need for frequent monitoring.[1] The most frequent side effect of dabigatran is bleeding, which can be treated using the highly effective antidote idarucizumab.[2] Several risk factors are known for dabigatran-related bleeding, primarily related to its pharmacokinetic properties.[3] Dabigatran is administered as a pro-drug, dabigatran etexilate, whose absorption is partly P-glycoprotein system-dependent and is converted into active dabigatran by esterases in the plasma.[2] Dabigatran clearance occurs predominantly (about 80%) via renal excretion. Its half-life is approximately 12-17 hours with normal renal function, but may double in case of severe renal impairment.[4] In our patient, the renal impairment will have contributed to the high dabigatran levels. Indeed, the risk of high levels of active dabigatran has been related to the level of renal impairment.

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Of concern is a recent study showing that 43% of patients on DOACs, including dabigatran, with a renal indication for dose reduction, receive standard dosing and that is therefore associated with a higher risk of major bleeding.[5]
Our patient also received amiodarone therapy, another important risk factor for bleeding when co-administrated with dabigatran.[1] Amiodarone increases dabigatran bioavailability by inhibiting P-glycoprotein synthesis and cytochrome P450, which decrease the elimination and increase the reabsorption of dabigatran etexilate. Other drug-drug interactions might have further contributed to the prolonged coagulation time. Namely, our patient was also on aliskiren and bisoprolol. Both medications have an influence on P-glycoprotein synthesis as well.[6,7] Finally, older age is another important risk factor for bleeding in our patient.[1]
Recently, the dabigatran-specific antidote idarucizumab became available for life-threatening bleeding or the need for emergency surgery in patients on dabigatran. Its binding to dabigatran, with an affinity 300 times stronger than thrombin, rapidly neutralises its anticoagulant effect.[3,8] In cases of sufficient dosing and normal renal function, idarucizumab eliminates the majority of the dabigatran effect, via renal clearance with dabigatran as a complex bound to idarucizumab. However, in the case of (prolonged) overdosing, dabigatran will have accumulated in extravascular compartments and a reappearance of anticoagulant activity will occur following initial idarucizumab reversal.[9] This rebound occurs when all intravascular unbound dabigatran is bound to idarucizumab, but the extravascular content is redistributed to the plasma when all idarucizumab stores are exhausted.[10] Such rebound may thus be caused by relatively low idarucizumab dosing or by significant extravascular accumulation after prolonged dabigatran overdosing.[9,11] In addition, the half-life of dabigatran is prolonged to 27 hours in renal failure, whereas idarucizumab has a half-life of approximately 10 hours, unaffected by renal dysfunction. This contributes to the rebound effects, requiring additional doses after several hours. The clinical course of our patient was complicated by multiple reappearances of rebounds, as illustrated in figure 1.
In our patient, the aPTT and PT were used as global screening tests for coagulation although both tests have low sensitivity to dabigatran. After idarucizumab administration, the aPTT and PT normalised, but were prolonged again after four hours, coinciding with continuous bleeding. Idarucizumab was administered twice thereafter, resulting in only a transient normalisation of clotting times (aPTT, PT and dTT). Unfortunately, the specific diluted thrombin time (dTT) was unavailable in our hospital but was measured in retrospect after three idarucizumab administrations. The dTT is specifically designed and calibrated for measurement of dabigatran levels, showing a direct relationship with drug concentrations.[11] The dTT level reflects the unbound active dabigatran in plasma, whereas the total dabigatran level (as measured by liquid chromatography-mass spectrometry) includes both the unbound dabigatran and the protein- or idarucizumab-bound inactive dabigatran.

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Total unbound dabigatran levels were measured in retrospect as well. In addition to the prolonged aPTT and PT, the active dabigatran level 72 hours after her last dabigatran dose was still extremely high (1271 ng/ml, target value <30 ng/ml). We later also measured a strong increase in total dabigatran (including dabigatran-idarucizumab complex) levels in the sample after first idarucizumab administration, only slowly decreasing after subsequent doses (figure 1). The normalisation of aPTT, PT and dTT (reversal of the anticoagulant effect) combined with high levels of total dabigatran shortly after idarucizumab administration illustrates its initial mechanism of action. The slow clearance of total dabigatran is most likely related to the slow renal clearance of the dabigatran-idarucizumab complex. The repeated prolongation of the aPTT, PT and dTT strongly suggests that an overload of dabigatran was redistributed into the plasma; its effect is no longer reversed causing a reoccurrence of the anticoagulant effect. This rebound effect can occur in up to 20-30% of patients, when initial dabigatran levels are high and/or renal insufficiency is present. Rebound that is associated with clinically relevant bleeding may be treated by repeated doses of idarucizumab.[10] In our patient, a rebound effect was observed even after repeated doses of idarucizumab, although with minimal clinical re-bleeding. Renal replacement therapy (RRT) is an alternative for dabigatran reversal in cases of a persisting rebound effect. Four hours of RRT can reduce dabigatran levels by up to 60%.[12] Therefore, RRT is suggested as therapy in case of dabigatran overdose together with mild to severe renal insufficiency. However, the slower dabigatran clearance rate as compared with the immediate effect of idarucizumab, the remaining possibility of rebound bleeding after cessation of RRT and its haemodynamic effects hamper RRT use in case of emergency surgery and haemodynamic instability.[13] Also, the bleeding risk associated with catheter insertion in a heavily anticoagulated patient must be taken into account. In our patient, RRT was deemed unfeasible because of her advanced deteriorating physical state. On day six, her situation further deteriorated with progressive shock and treatment-resistant pain. In line with the patient’s wishes, the medical team initiated palliative care and she succumbed shortly after. Autopsy was performed, showing signs of multi-organ failure with a large ulcerative area in the rectum suspected of acute ischaemic colitis. No definitive other infectious or bleeding sources were found.
A suggested algorithm for clinical decision-making on dabigatran reappearance is proposed in figure 2. In conclusion, our patient presented with haemarthrosis of the right shoulder. Dabigatran was stopped and she underwent surgery because of an infected shoulder joint, which was complicated by severe bleeding due to dabigatran overdose. Idarucizumab was administered yet resulted in only temporary undetectable levels of dabigatran and normalisation of coagulation tests, most likely caused by a dabigatran rebound effect. Despite repeated administrations of idarucizumab, the bleeding continued and coagulation times were again prolonged.

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Acknowledgments
Daan van de Kerkhof (Department of Clinical Biochemistry, Catharina Hospital, Eindhoven, the Netherlands) for performing the liquid chromatography-mass spectrometry and Huib Ceelie (Department of Laboratory Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands) for the logistics.

Disclosures
All authors declare no conflict of interest. No funding or financial support was received.

Informed consent was obtained from the patient’s legal representative for the publication of this case report.

References:

  1. Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost. 2009;15 Suppl 1:9S-16S.
  2. Eikelboom JW, Quinlan DJ, van Ryn J, Weitz JI. Idarucizumab: The Antidote for Reversal of Dabigatran. Circulation. 2015;132:2412-22.
  3. Glund S, Coble K, Gansser D, et al. Pharmacokinetics of idarucizumab and its target dabigatran in patients requiring urgent reversal of the anticoagulant effect of dabigatran. J Thromb Haemost. 2019;17:1319-28.
  4. Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014;63:321-8.
  5. Yao X, Shah ND, Sangaralingham LR, Gersh BJ, Noseworthy PA. Non-Vitamin K Antagonist Oral Anticoagulant Dosing in Patients With Atrial Fibrillation and Renal Dysfunction. J Am Coll Cardiol. 2017;69:2779-90.
  6. Vaidyanathan S, Camenisch G, Schuetz H, et al. Pharmacokinetics of the oral direct renin inhibitor aliskiren in combination with digoxin, atorvastatin, and ketoconazole in healthy subjects: the role of P-glycoprotein in the disposition of aliskiren. J Clin Pharmacol. 2008;48:1323-38.
  7. Nehaj F, Sokol J, Ivankova J, Mokan M, Mokan M. Effect of Bisoprolol on the Level of Dabigatran. Am J Ther. 2020;27:e159-e64.
  8. Glund S, Stangier J, Schmohl M, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet. 2015;386:680-90.
  9. Stecher A, Vene N, Mavri A, Mijovski MB, Krevel B, Gradisek P. Late rebound of dabigatran levels after idarucizumab reversal in two patients with severe renal failure. Eur J Anaesthesiol. 2017;34:400-2.
  10. Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal – Full Cohort Analysis. N Engl J Med. 2017;377:431-41.
  11. Gendron N, Gay J, Lemoine M, Gaussem P, Lillo-Le-Louet A, Smadja DM. Usefulness of initial plasma dabigatran concentration to predict rebound after reversal. Haematologica. 2018;103:e226-e9.
  12.  Wychowski MK, Kouides PA. Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment. Ann Pharmacother. 2012;46:e10.
  13. Fuhr LM, Hanke N, Meibohm B, Lehr T. Effective Removal of Dabigatran by Idarucizumab or Hemodialysis: A Physiologically Based Pharmacokinetic Modeling Analysis. Clin Pharmacokinet. 2020;59:809-25.