Correspondence Dabigatran-Associated Spontaneous Acute Cervical Epidural Hematoma LETTER: of dabigatran is rapidly increasing since it was approved T heas anuseeffective alternative to vitamin K antagonists in patients
with atrial fibrillation as it produces a predictable pharmacodynamic effect without the need for coagulation monitoring. (1, 4, 6-8) Many caregivers however are not yet familiar with the use and complications of dabigatran. Although the risk of intracranial hemorrhage is reduced with dabigatran, urgent management of major bleedings is still problematic.
prolonged (47.6 seconds). In an attempt to reverse the effects of dabigatran, prothrombin complex concentrate (2000 IU) was administered corresponding to 25 IU/kg as proposed in international guidelines. Urgent posterior cervical laminectomy (C2 C3 C4) with hematoma removal was performed (Figure 2). Bipolar coagulation, a gelatin-thrombin-matrix, and a cellulose matrix were used to obtain adequate local hemostasis. The surgical procedure and the postoperative course were uneventful, with complete neurological recovery obtained by the patient.
We present a 70-year-old male patient with atrial fibrillation on dabigatran therapy (150 mg bid) who presented with acute severe cervical pain quickly followed by tetraplegia, sensory loss, and severe autonomic instability 12 hours after his last dabigatran intake. Urgent computed tomography imaging revealed an acute epidural hematoma at the C2 C3 C4 level (Figure 1). The patient weighed 80 kg. Renal function was normal (estimated glomerular filtration rate: 85 mL/min/1.73 m2), blood platelet count was 143 109/L, and activated partial thromboplastin time was
Dabigatran competitively, selectively, and reversibly inhibits thrombin/factor IIa (which enables conversion of fibrinogen into fibrin). The effects of dabigatran parallel its time to peak concentration and elimination half-life. Dabigatran has an 80% renal excretion profile, a 35% protein binding, and in patients with a normal renal function, its elimination half-life ranges from 12 to 17 hours. A main issue with dabigatran involves a difficult clinical assessment of the coagulation status and the fact that no reliable reversal agents have been identified (1-8). The future in this regard, however, is promising because recently data on the identification, humanization, and in vitro pharmacology of an antidote
Figure 1. Computed tomographic image of the acute epidural hematoma at the C2 C3 C4 level.
Figure 2. Computed tomographic image after hematoma removal.
WORLD NEUROSURGERY 83 [2]: 257-260, FEBRUARY 2015
www.WORLDNEUROSURGERY.org
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CORRESPONDENCE
for dabigatran (aDabi-Fab) have been published and studies are ongoing (5). Best literature recommendations regarding dabigatran include the discontinuation of therapy 1 2 days ahead of invasive procedures in patients with normal kidney function and 3 5 days in patients with impaired renal function. In patients in whom urgent surgery is mandated, no valid reversal treatment exists to date. A number of strategies have been proposed, and preclinical data suggest that prothrombin complex concentrates are a reasonable approach in an attempt to overcome the effect of dabigatran as a factor IIa inhibitor by raising the levels of vitamin K dependent factors to supranormal levels. Hemodialysis may be considered for emergency reversal of dabigatran-induced anticoagulation, although it can be difficult to perform in a hemodynamically unstable patient, as it was the case in our 70-year-old patient who also suffered from autonomic instability (1-8). A consensus regarding the reversal of dabigatran-induced anticoagulation has not been reached yet. In the acute setting, we would recommend the discontinuation of dabigatran, meticulous local hemostatic control, and the use of prothrombin complex concentrate. Caregivers in general and neurologists and neurosurgeons in particular need to be aware of the possible complications of these newer oral anticoagulants. Sven Bamps1, Tomas Decramer1, Nicolas Vandenbussche2, Peter Verhamme3, Vincent Thijs2, Johan Van Loon1, Tom Theys1 From the 1KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurosurgery and Neuroanatomy, University Hospitals Leuven; 2KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, University Hospitals Leuven, Department of Neurology, VIB - Vesalius Research Center; and 3KU Leuven - University of Leuven, Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, University Hospitals Leuven, Department of Internal Medicine, Leuven, Belgium To whom correspondence should be addressed: Sven Bamps, M.D. [E-mail: [email protected]] Published online 16 October 2014; http://dx.doi.org/10.1016/j.wneu.2014.10.012.
REFERENCES 1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139-1151, 2009. 2. Diaz M, Borobia A, Nuñez M, Virto A, Fabra S, Casado M, García-Erce J, Samama C: Use of prothrombin complex concentrates for urgent reversal of dabigatran in the emergency department. Haematologica 98:e143-e144, 2013. 3. Dickneite G, Hoffman M: Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost 111:189-198, 2014. 4. Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P: EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 34: 2094-2106, 2013. 5. Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, Nar H, Litzenburger T: A specific antidote for dabigatran: functional and structural characterization. Blood 121:3554-3562, 2013. 6. Stangier J, Clemens A: Pharmacology, pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost 15(Suppl 1):9S-16S, 2009. 7. Truumees E, Gaudu T, Dieterichs C, Geck M, Stokes D: Epidural hematoma and intraoperative hemorrhage in a spine trauma patient on Pradaxa (Dabigatran). Spine 37:E863-E865, 2012.
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8. van Ryn J, Stangier J, Haertter S, Liesenfeld K-H, Wienen W, Feuring M, Clemens A: Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 103:1116-1127, 2010.
Vasospasm in Aneurysmal Subarachnoid Hemorrhage: An Evolving Knowledge read with great interest the paper by Billingsley et al. (1) on I have vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). It has been reported widely that cerebral vasospasm and the resulting cerebral ischemia occurring after subarachnoid hemorrhage (SAH) are responsible for the considerable morbidity and mortality in patients affected by cerebral aneurysms. In their article Billingsley et al. (1) have raised an important question from their accumulating data about cerebral vasospasm. Emerging data on vasospasm after SAH hold promise in changing what we still believe about such SAH-related complications. During the last century, a great consensus existed that cerebral vasospasm was the most important determinant of poor prognosis in patients with aSAH. Accordingly, many pharmacologic interventions have been assessed in experimental studies and unsuccessful clinical trials addressed to counteract the spastic activity of the cerebral arterial vessel. During the last decade, accumulating experimental and clinical evidence has demonstrated that the presence of delayed vasospasm of the major cerebral vessels may just be a contributing factor but not necessarily the principal determinant of delayed cerebral ischemia and delayed ischemic neurologic deficit. Cerebral infarction can occur when vasospasm is not angiographically detected in the territorial artery (2), and poor outcome in aSAH seems to be directly dependent on infarction but independent of vasospasm (5). There is increasing evidence that other contributing factors may be involved in the development of delayed cerebral ischemia, and their characterization and treatment could improve the consistently poor clinical outcome in patients with aSAH. It has been pointed out that may be an early, short-lived phase occurring immediately after SAH and a subsequent phase that is prolonged or chronic (3). Both phases of vasospasm are considered to result from an abnormal constriction of the muscular layers of both microcirculatory vessels and proximal vessel and have been considered the main cause of cerebral ischemia after SAH. However, whether the 2 phases are independent or interactive with respect to the clinical course has not been settled. Taken collectively, the role of vasospasm has probably been misinterpreted; therefore, treating vasospasm alone probably targets the wrong cause and may not lead to improvement in functional
Key words Aneurysmal subarachnoid hemorrhage - Cerebral vasospasm -
Abbreviations and Acronyms aSAH: Aneurysmal subarachnoid hemorrhage SAH: Subarachnoid hemorrhage
83 [2]: 257-260, FEBRUARY 2015 WORLD NEUROSURGERY
with atrial fibrillation as it produces a predictable pharmacodynamic effect without the need for coagulation monitoring. (1, 4, 6-8) Many caregivers however are not yet familiar with the use and complications of dabigatran. Although the risk of intracranial hemorrhage is reduced with dabigatran, urgent management of major bleedings is still problematic.
prolonged (47.6 seconds). In an attempt to reverse the effects of dabigatran, prothrombin complex concentrate (2000 IU) was administered corresponding to 25 IU/kg as proposed in international guidelines. Urgent posterior cervical laminectomy (C2 C3 C4) with hematoma removal was performed (Figure 2). Bipolar coagulation, a gelatin-thrombin-matrix, and a cellulose matrix were used to obtain adequate local hemostasis. The surgical procedure and the postoperative course were uneventful, with complete neurological recovery obtained by the patient.
We present a 70-year-old male patient with atrial fibrillation on dabigatran therapy (150 mg bid) who presented with acute severe cervical pain quickly followed by tetraplegia, sensory loss, and severe autonomic instability 12 hours after his last dabigatran intake. Urgent computed tomography imaging revealed an acute epidural hematoma at the C2 C3 C4 level (Figure 1). The patient weighed 80 kg. Renal function was normal (estimated glomerular filtration rate: 85 mL/min/1.73 m2), blood platelet count was 143 109/L, and activated partial thromboplastin time was
Dabigatran competitively, selectively, and reversibly inhibits thrombin/factor IIa (which enables conversion of fibrinogen into fibrin). The effects of dabigatran parallel its time to peak concentration and elimination half-life. Dabigatran has an 80% renal excretion profile, a 35% protein binding, and in patients with a normal renal function, its elimination half-life ranges from 12 to 17 hours. A main issue with dabigatran involves a difficult clinical assessment of the coagulation status and the fact that no reliable reversal agents have been identified (1-8). The future in this regard, however, is promising because recently data on the identification, humanization, and in vitro pharmacology of an antidote
Figure 1. Computed tomographic image of the acute epidural hematoma at the C2 C3 C4 level.
Figure 2. Computed tomographic image after hematoma removal.
WORLD NEUROSURGERY 83 [2]: 257-260, FEBRUARY 2015
www.WORLDNEUROSURGERY.org
257
CORRESPONDENCE
for dabigatran (aDabi-Fab) have been published and studies are ongoing (5). Best literature recommendations regarding dabigatran include the discontinuation of therapy 1 2 days ahead of invasive procedures in patients with normal kidney function and 3 5 days in patients with impaired renal function. In patients in whom urgent surgery is mandated, no valid reversal treatment exists to date. A number of strategies have been proposed, and preclinical data suggest that prothrombin complex concentrates are a reasonable approach in an attempt to overcome the effect of dabigatran as a factor IIa inhibitor by raising the levels of vitamin K dependent factors to supranormal levels. Hemodialysis may be considered for emergency reversal of dabigatran-induced anticoagulation, although it can be difficult to perform in a hemodynamically unstable patient, as it was the case in our 70-year-old patient who also suffered from autonomic instability (1-8). A consensus regarding the reversal of dabigatran-induced anticoagulation has not been reached yet. In the acute setting, we would recommend the discontinuation of dabigatran, meticulous local hemostatic control, and the use of prothrombin complex concentrate. Caregivers in general and neurologists and neurosurgeons in particular need to be aware of the possible complications of these newer oral anticoagulants. Sven Bamps1, Tomas Decramer1, Nicolas Vandenbussche2, Peter Verhamme3, Vincent Thijs2, Johan Van Loon1, Tom Theys1 From the 1KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurosurgery and Neuroanatomy, University Hospitals Leuven; 2KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, University Hospitals Leuven, Department of Neurology, VIB - Vesalius Research Center; and 3KU Leuven - University of Leuven, Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, University Hospitals Leuven, Department of Internal Medicine, Leuven, Belgium To whom correspondence should be addressed: Sven Bamps, M.D. [E-mail: [email protected]] Published online 16 October 2014; http://dx.doi.org/10.1016/j.wneu.2014.10.012.
REFERENCES 1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139-1151, 2009. 2. Diaz M, Borobia A, Nuñez M, Virto A, Fabra S, Casado M, García-Erce J, Samama C: Use of prothrombin complex concentrates for urgent reversal of dabigatran in the emergency department. Haematologica 98:e143-e144, 2013. 3. Dickneite G, Hoffman M: Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost 111:189-198, 2014. 4. Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P: EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 34: 2094-2106, 2013. 5. Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, Nar H, Litzenburger T: A specific antidote for dabigatran: functional and structural characterization. Blood 121:3554-3562, 2013. 6. Stangier J, Clemens A: Pharmacology, pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost 15(Suppl 1):9S-16S, 2009. 7. Truumees E, Gaudu T, Dieterichs C, Geck M, Stokes D: Epidural hematoma and intraoperative hemorrhage in a spine trauma patient on Pradaxa (Dabigatran). Spine 37:E863-E865, 2012.
258
www.SCIENCEDIRECT.com
8. van Ryn J, Stangier J, Haertter S, Liesenfeld K-H, Wienen W, Feuring M, Clemens A: Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 103:1116-1127, 2010.
Vasospasm in Aneurysmal Subarachnoid Hemorrhage: An Evolving Knowledge read with great interest the paper by Billingsley et al. (1) on I have vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). It has been reported widely that cerebral vasospasm and the resulting cerebral ischemia occurring after subarachnoid hemorrhage (SAH) are responsible for the considerable morbidity and mortality in patients affected by cerebral aneurysms. In their article Billingsley et al. (1) have raised an important question from their accumulating data about cerebral vasospasm. Emerging data on vasospasm after SAH hold promise in changing what we still believe about such SAH-related complications. During the last century, a great consensus existed that cerebral vasospasm was the most important determinant of poor prognosis in patients with aSAH. Accordingly, many pharmacologic interventions have been assessed in experimental studies and unsuccessful clinical trials addressed to counteract the spastic activity of the cerebral arterial vessel. During the last decade, accumulating experimental and clinical evidence has demonstrated that the presence of delayed vasospasm of the major cerebral vessels may just be a contributing factor but not necessarily the principal determinant of delayed cerebral ischemia and delayed ischemic neurologic deficit. Cerebral infarction can occur when vasospasm is not angiographically detected in the territorial artery (2), and poor outcome in aSAH seems to be directly dependent on infarction but independent of vasospasm (5). There is increasing evidence that other contributing factors may be involved in the development of delayed cerebral ischemia, and their characterization and treatment could improve the consistently poor clinical outcome in patients with aSAH. It has been pointed out that may be an early, short-lived phase occurring immediately after SAH and a subsequent phase that is prolonged or chronic (3). Both phases of vasospasm are considered to result from an abnormal constriction of the muscular layers of both microcirculatory vessels and proximal vessel and have been considered the main cause of cerebral ischemia after SAH. However, whether the 2 phases are independent or interactive with respect to the clinical course has not been settled. Taken collectively, the role of vasospasm has probably been misinterpreted; therefore, treating vasospasm alone probably targets the wrong cause and may not lead to improvement in functional
Key words Aneurysmal subarachnoid hemorrhage - Cerebral vasospasm -
Abbreviations and Acronyms aSAH: Aneurysmal subarachnoid hemorrhage SAH: Subarachnoid hemorrhage
83 [2]: 257-260, FEBRUARY 2015 WORLD NEUROSURGERY
