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Spontaneous splenic hemorrhage after initiation of dabigatran (Pradaxa) for atrial fibrillation
American Journal of Emergency Medicine (2012) 30, 2082.e1–2082.e2
www.elsevier.com/locate/ajem
Case Report Spontaneous splenic hemorrhage after initiation of dabigatran (Pradaxa) for atrial fibrillation☆ Abstract Dabigatran etexilate (Pradaxa; Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT) is an oral anticoagulant that produces a reliable, dose-dependent anticoagulant effect without the need for routine laboratory monitoring. Dabigatran is a direct thrombin inhibitor, acting like other members in its class (bivalirudin, argatroban) to impede the clotting process through selective and reversible binding with both free and clot-bound thrombin. Dabigatran anticoagulates rapidly: plasma levels peak 2 hours after absorption, with a half-life that ranges between 12 and 17 hours. Dabigatran was approved by the Food and Drug Administration in October 2010 after it compared favorably with warfarin in a large clinical trial studying its efficacy in stroke prevention in atrial fibrillation. Currently, there is no laboratory test on the market by which a physician can quantify the anticoagulation effect of dabigatran, nor is there any antidote to reverse a life-threatening bleed should it occur. We present a case of a patient with splenic hemorrhagic soon after initiation of dabigatran. A 78-year-old woman with a medical history that included coronary artery disease, aortic valve stenosis, diabetes, peripheral vascular disease, renal artery stenosis, and embolic stroke from atrial fibrillation presented to the emergency department (ED) for evaluation of acute abdominal pain. One week before her ED presentation, the patient's primary physician had changed her anticoagulation regimen from warfarin to dabigatran 100 mg orally every 12 hours. The patient's pain began shortly before her presentation; she described it as an upper abdominal pressure that did not radiate. The pain was associated with decreased appetite, nausea, and nonbloody, nonbilious vomiting. The patient denied any history of trauma. The remainder of the review of systems was negative. The initial vital signs in the ED demonstrated that she was afebrile (98.8°F), with a blood pressure of 118/64 mm Hg, a pulse of 62 beats/min, a respiratory rate of 16 breaths/min, ☆
There is no outside funding or support.
0735-6757/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
and an oxygen saturation on room air of 100%. Physical examination was significant for a woman in moderate distress due to pain. Cardiac examination demonstrated irregularly irregular heart sounds with a 3/6 systolic murmur over the aortic valve. Abdominal examination revealed moderate tenderness to palpation over her epigastric area. Repeat examination 2 hours later (at change of shift) demonstrated increasing tenderness and rigidity of the upper abdomen. Complete blood count revealed a hemoglobin level of 8.3 g/dL, a hematocrit of 25.4%, a white blood cell count of 10.59 × 103/μL, and a platelet count of 192 × 103/μL. Coagulation studies were all elevated: the prothrombin time was 18.6 seconds, international normalized ratio was 1.5, and the partial thromboplastin time was 62.5 seconds. The blood biochemistry analyses were as follows: Na, 134 mmol/L; K, 4.1 mmol/L; Cl, 98 mmol/L; CO2, 28.9 mmol/L; blood urea nitrogen, 20 mg/dL; Cr, 1.1 mg/dL; glucose, 227 mg/dL; Ca, 9.1 mg/dL. The liver function tests and urinalysis were also within normal limits. An intravenous/oral contrast computed tomography scan of the abdomen demonstrated active extravasation of contrast from the posterior aspect of the spleen with consequent hemoperitoneum. The patient was soon given 2 units of fresh-frozen plasma and 2 units of packed red blood cells in preparation for the interventional radiology suite, where she underwent embolization and coiling of the splenic artery. She was then transferred to the intensive care unit for continued resuscitation. Although it is possible to overcoagulate with dabigatran, there is no easy or accurate method to quantify its anticoagulant effect. Dabigatran does prolong the activated partial thromboplastin time but does so unreliably and has little impact on the prothrombin time and the international normalized ratio at typical clinically relevant plasma concentrations [1-4]. Other coagulation assays require further clinical evaluation, are imperfect in their current state, or are not commercially available [2]. Dabigatran has no readily available reversal agent. Its short (12 hour) duration of action in patients with normal renal function means that, for most patients with minor bleeding, withdrawal of the drug and local measures will be sufficient to treat the episode [5]. The use of fresh-frozen plasma as a reversal agent is limited both by the small amount of thrombin it contains and the lack of evidence for its use [6].
2082.e2 Dialysis may be the best option: with roughly 80% excreted by the kidney and only 35% plasma protein bound, dabigatran appears easily removed via dialysis (62% at 2 hours) [7,8]. There are no case reports of splenic hemorrhage secondary to dabigatran use; presumably, this is a rare event. However, because more patients begin to use this novel anticoagulant, physicians should be diligent in reporting complications to allow further assessment of its safety.
Charles Haviland Moore MD Jonathan Snashall MD Keith Boniface MD, RDMS James Scott MD Department of Emergency Medicine George Washington University Medical Center Washington, DC 20037 E-mail address: [email protected]
http://dx.doi.org/10.1016/j.ajem.2011.10.031
Case Report
References [1] Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51. [2] van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103(6):1116-27. [3] Beasley BN, Unger EF, Temple R. Anticoagulant options—why the FDA approved a higher but not a lower dose of dabigatran. N Engl J Med 2011;364(19):1788-90. [4] Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors development. Clin Pharmacokinet 2009;48:1-22. [5] Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008;36:386-99. [6] Crowther MA, Warkentin TE. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemostasis 2009;7(Suppl. 1):107-10. [7] Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N. Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats. Thromb Haemost 2007;98:333-8. [8] Stangier J, Rathgen K, Stähle H, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate. Clin Pharmacokinet 2010;49:259-68.
www.elsevier.com/locate/ajem
Case Report Spontaneous splenic hemorrhage after initiation of dabigatran (Pradaxa) for atrial fibrillation☆ Abstract Dabigatran etexilate (Pradaxa; Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT) is an oral anticoagulant that produces a reliable, dose-dependent anticoagulant effect without the need for routine laboratory monitoring. Dabigatran is a direct thrombin inhibitor, acting like other members in its class (bivalirudin, argatroban) to impede the clotting process through selective and reversible binding with both free and clot-bound thrombin. Dabigatran anticoagulates rapidly: plasma levels peak 2 hours after absorption, with a half-life that ranges between 12 and 17 hours. Dabigatran was approved by the Food and Drug Administration in October 2010 after it compared favorably with warfarin in a large clinical trial studying its efficacy in stroke prevention in atrial fibrillation. Currently, there is no laboratory test on the market by which a physician can quantify the anticoagulation effect of dabigatran, nor is there any antidote to reverse a life-threatening bleed should it occur. We present a case of a patient with splenic hemorrhagic soon after initiation of dabigatran. A 78-year-old woman with a medical history that included coronary artery disease, aortic valve stenosis, diabetes, peripheral vascular disease, renal artery stenosis, and embolic stroke from atrial fibrillation presented to the emergency department (ED) for evaluation of acute abdominal pain. One week before her ED presentation, the patient's primary physician had changed her anticoagulation regimen from warfarin to dabigatran 100 mg orally every 12 hours. The patient's pain began shortly before her presentation; she described it as an upper abdominal pressure that did not radiate. The pain was associated with decreased appetite, nausea, and nonbloody, nonbilious vomiting. The patient denied any history of trauma. The remainder of the review of systems was negative. The initial vital signs in the ED demonstrated that she was afebrile (98.8°F), with a blood pressure of 118/64 mm Hg, a pulse of 62 beats/min, a respiratory rate of 16 breaths/min, ☆
There is no outside funding or support.
0735-6757/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
and an oxygen saturation on room air of 100%. Physical examination was significant for a woman in moderate distress due to pain. Cardiac examination demonstrated irregularly irregular heart sounds with a 3/6 systolic murmur over the aortic valve. Abdominal examination revealed moderate tenderness to palpation over her epigastric area. Repeat examination 2 hours later (at change of shift) demonstrated increasing tenderness and rigidity of the upper abdomen. Complete blood count revealed a hemoglobin level of 8.3 g/dL, a hematocrit of 25.4%, a white blood cell count of 10.59 × 103/μL, and a platelet count of 192 × 103/μL. Coagulation studies were all elevated: the prothrombin time was 18.6 seconds, international normalized ratio was 1.5, and the partial thromboplastin time was 62.5 seconds. The blood biochemistry analyses were as follows: Na, 134 mmol/L; K, 4.1 mmol/L; Cl, 98 mmol/L; CO2, 28.9 mmol/L; blood urea nitrogen, 20 mg/dL; Cr, 1.1 mg/dL; glucose, 227 mg/dL; Ca, 9.1 mg/dL. The liver function tests and urinalysis were also within normal limits. An intravenous/oral contrast computed tomography scan of the abdomen demonstrated active extravasation of contrast from the posterior aspect of the spleen with consequent hemoperitoneum. The patient was soon given 2 units of fresh-frozen plasma and 2 units of packed red blood cells in preparation for the interventional radiology suite, where she underwent embolization and coiling of the splenic artery. She was then transferred to the intensive care unit for continued resuscitation. Although it is possible to overcoagulate with dabigatran, there is no easy or accurate method to quantify its anticoagulant effect. Dabigatran does prolong the activated partial thromboplastin time but does so unreliably and has little impact on the prothrombin time and the international normalized ratio at typical clinically relevant plasma concentrations [1-4]. Other coagulation assays require further clinical evaluation, are imperfect in their current state, or are not commercially available [2]. Dabigatran has no readily available reversal agent. Its short (12 hour) duration of action in patients with normal renal function means that, for most patients with minor bleeding, withdrawal of the drug and local measures will be sufficient to treat the episode [5]. The use of fresh-frozen plasma as a reversal agent is limited both by the small amount of thrombin it contains and the lack of evidence for its use [6].
2082.e2 Dialysis may be the best option: with roughly 80% excreted by the kidney and only 35% plasma protein bound, dabigatran appears easily removed via dialysis (62% at 2 hours) [7,8]. There are no case reports of splenic hemorrhage secondary to dabigatran use; presumably, this is a rare event. However, because more patients begin to use this novel anticoagulant, physicians should be diligent in reporting complications to allow further assessment of its safety.
Charles Haviland Moore MD Jonathan Snashall MD Keith Boniface MD, RDMS James Scott MD Department of Emergency Medicine George Washington University Medical Center Washington, DC 20037 E-mail address: [email protected]
http://dx.doi.org/10.1016/j.ajem.2011.10.031
Case Report
References [1] Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51. [2] van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103(6):1116-27. [3] Beasley BN, Unger EF, Temple R. Anticoagulant options—why the FDA approved a higher but not a lower dose of dabigatran. N Engl J Med 2011;364(19):1788-90. [4] Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors development. Clin Pharmacokinet 2009;48:1-22. [5] Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008;36:386-99. [6] Crowther MA, Warkentin TE. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemostasis 2009;7(Suppl. 1):107-10. [7] Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N. Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats. Thromb Haemost 2007;98:333-8. [8] Stangier J, Rathgen K, Stähle H, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate. Clin Pharmacokinet 2010;49:259-68.