Correspondence
Activated prothrombin complex concentrate for dabigatran-associated bleeding subdural haematoma with associated midline shift (Fig 2). The last dose of dabigatran, 110 mg, was 2 d before transfer to our hospital. On admission the thrombin time (TT) was 127 s (normal range 20–30 s), activated partial thromboplastin time (aPTT) was 46 s (normal 22–35 s), prothrombin time – international normalized ratio (INR) was 12, dabigatran concentration (with Hemoclot) was 50 ng/ml, and creatinine 135 lmol/l with calculated creatinine clearance of 45 ml/min. The neurosurgeon elected to defer haematoma drainage until dabigatran had been eliminated. The patient received 4600 units (50 units/kg) of aPCC, whereafter the weakness improved without immediate change in the coagulation profile. The thrombin time normalized 3 d later and he underwent uneventful craniotomy with evacuation of 100 ml of blood. Repeat imaging demonstrated resolution of the bleed and he was discharged home the next day. At 1month follow-up, there was complete resolution of the weakness. An 81-year-old female (Hamilton 2) with atrial fibrillation and hypertension woke up in the morning, 12 h after her last dabigatran dose (110 mg), and felt normal but 1 h later she fell off the toilet and was disoriented, unsteady and had right-sided weakness and slurred speech. When the paramedics arrived, 20 min later, her blood pressure was 196/100. CT, 70 min after onset showed acute intra-axial haemorrhage
A humanized antibody fragment to reverse the oral thrombin inhibitor dabigatran is currently under development (Schiele et al, 2013). The absence of a specific reversal agent has caused apprehension over the use of this anticoagulant (Cotton et al, 2011). Prothrombin complex concentrate (PCC) and activated factor VII seemed ineffective in recently reported cases (Lillo-Le Louet et al, 2012), and animal models and ex vivo studies have provided conflicting results Majeed & Schulman, 2013). Although dabigatran has a low degree of binding to plasma proteins and is dialyzable (Khadzhynov et al, 2013), it may take many hours to eliminate this drug from the circulation. We treated four patients with potentially life-threatening dabigatran-associated bleeding with activated PCC (FEIBA, Baxter AG, Vienna, Austria), two in Hamilton, Ontario and two in Edmonton, Alberta. The laboratory and transfusion data are shown in Fig 1. Creatinine clearance was estimated with the Cockroft-Gault formula. An 84-year-old male (Hamilton 1) with a medical history of atrial fibrillation, hypertension and chronic renal insufficiency was urgently referred to our tertiary care hospital with subdural haematoma. He had fallen at home 1 month earlier and, at the time of presentation, had a 3-day history of headache and progressive left sided weakness. Computed tomography (CT) showed acute on chronic right parietal
160
Hamilton 1 140 aPTT or TT, s
aPTT or TT, s
aPTT TT
120
Hamilton 2
140
100 80 60 40 20
aPTT TT
120 100 80 60 40 20
0
0
0
24
48
72
96
120
0
140
Edmonton 1
aPTT or TT, s
120 100 80 60 40 20
72 96 120 144
120
Edmonton 2
100 80 60 40 20 0
0 0
24
48
72
96
120 144 168 192
Hours after last dose dabigatran
308
aPTT TT Hb
140 aPTT or TT, s; Hb, g/l
aPTT TT Hgb
24 48
Hours after last dose of dabigatran
Hours after last dose dabigatran
0
24
48
72
96 120 144 168
Hours (est.) after last dose dabigatran
Fig 1. Evolution of activated partial thromboplastin time (aPTT), thrombin time (TT), haemoglobin concentration (Hb; for the cases with external blood loss) in relation to the last dose of dabigatran. Symbols with an attached upward arrow indicate ‘more than the upper limit of the analysed range’. A blue downward arrow indicates infusion of activated prothrombin complex concentrate. Red downward arrows indicate red cell transfusions.
ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2013, 164, 296–310
Correspondence
Fig 2. Computed tomography scan showing 35 cm right parietal subdural haematoma with 13 mm of midline shift, compression of the right lateral ventricle and mild uncal herniation.
in the left basal ganglia, 18 9 23 9 33 cm with mild perilesional oedema and chronic microangiopathy. Her creatinine was 84 lmol/l, corresponding to a calculated creatinine clearance of 43 ml/min, aPTT was 48 s (normal 22–35 s) and TT >150 s (normal 20–30 s). She received aPCC 2500 units (42 units/kg) starting 4 h after onset. Repeat imaging after 3 d showed a mild increase in the haematoma (22 9 30 9 38 cm). There was no further progression of her symptoms; her speech normalized on the day of admission but her motor function required 2 months of rehabilitation. At follow-up, 13 weeks after the event, she had normal mobility and strength but slight numbness on her right side. An 85-year-old female (Edmonton 1) with atrial fibrillation, hypertension, dyslipidaemia, chronic kidney disease and previous myocardial infarction required insertion of a dual-chamber pacemaker due to sinus node tachy-bradydysfunction and 7s-pauses. The patient was on aspirin 81 mg. After the insertion, dabigatran was started at 75 mg b.i.d. due to a calculated creatinine clearance of 27 ml/min. The creatinine subsequently increased from 160 to 424 lmol/l, the patient became hypotensive and an echocardiogram demonstrated penetration of a pacemaker lead into the pericardium, where there was a circumferential effusion. The aPTT was 65 s but pericardiocentesis was of vital importance, so 100 units/kg of aPCC was infused, immediately followed by centesis, draining 700 ml of blood. The bleeding ceased but the thrombin time remained unmeasurable for three more days. An 83-year-old female (Edmonton 2) with atrial fibrillation was admitted for upper gastrointestinal bleeding; haemoglobin concentration (Hb) was 99 g/l and creatinine clearance 24 ml/min. Dabigatran, started 1 month earlier at 110 mg b.i.d. (creatinine clearance then 43 ml/min), was withheld but her Hb continued to decrease, to 70 g/l ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2013, 164, 296–310
after 3 d. Upper endoscopy was performed to verify the bleeding, aPCC at a dose of 50 units/kg and 3 units of red cells were administered and the clinical condition stabilized. These cases illustrate how life-threatening dabigatranassociated bleeding might be controlled with aPCC, supported by another case (Dager et al, 2013). These reports are admittedly anecdotal but still of interest whilst awaiting specifically designed clinical studies. The mechanism of action is unclear but might entail boosting the prothrombinase complex on the platelet surface (Hoffman & Dargaud, 2012). Alternatively, high levels of prothrombin increase the velocity of thrombin generation (Hoffman & Dargaud, 2012). aPCC does not remove dabigatran, explaining the unchanged thrombin time. With the retrospective nature of data collection, our laboratory data are limited. Discrepant haemostatic and laboratory results were also seen in animal models (van Ryn et al, 2011), and in healthy volunteers receiving dabigatran, aPCC corrected all parameters of thrombin generation (Majeed & Schulman, 2013). In a study with another thrombin inhibitor, melagatran, aPCC reduced blood loss in the rat tail bleeding model (Elg et al, 2001a). In comparison with other haemostatic agents, aPCC seemed to be the most effective for shortening the bleeding time in animals exposed to high doses of melagatran (Elg et al, 2001b). Doses of aPCC corresponding to 80–160 units/kg corrected some of the thrombin generation parameters to supranormal levels in the above-mentioned ex vivo study ((Majeed & Schulman, 2013) and therefore it might be prudent to attempt reversal in clinical situations with only 50 units/kg, which is at the lower end of the dose range used in haemophilia with inhibitors. Further studies are required to confirm the benefits and identify harms of aPCC in dabigatran-associated major bleeding.
Author contributions BR, SN, MA and SG managed the cases and provided the data, SS and JKG wrote the manuscript, all co-authors read critically and revised the manuscript.
Competing interests SS has received honoraria from Boehringer Ingelheim for work in study committees. Sam Schulman1 Bruce Ritchie2 Jennifer K. Goy1 Susan Nahirniak3 Mohammad Almutawa4 Shari Ghanny1 1
Department of Medicine, McMaster University, Hamilton, ON,
2
Department of Medicine, University of Alberta, 3Department of
309
Correspondence Laboratory Medicine and Pathology, University of Alberta, and
Keywords: dabigatran, bleeding activated prothrombin complex
4
concentrate
Division of Cardiology, Mazankowski Heart Institute, University of
Alberta, Edmonton, AB, Canada E-mail: [email protected]
First published online 23 October 2013 doi: 10.1111/bjh.12620
References Cotton, B.A., McCarthy, J.J. & Holcomb, J.B. (2011) Acutely injured patients on dabigatran. New England Journal of Medicine, 365, 2039–2040. Dager, W.E., Gosselin, R.C. & Roberts, A.J. (2013) Reversing dabigatran in a life-threatening bleed occurring during cardiac ablation with factor eight inhibitor bypassing activity. Critical Care Medicine, 41, e42–e46. Elg, M., Carlsson, S. & Gustafsson, D. (2001a) Effects of activated prothrombin complex concentrate or recombinant factor VIIa on bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor. Thrombosis Research, 101, 145–157. Elg, M., Carlsson, S. & Gustafsson, D. (2001b) Effects of agents, used to treat bleeding disorders,
310
on bleeding time prolonged by a very high dose of a direct thrombin inhibitor in anesthesized rats and rabbits. Thrombosis Research, 101, 159–170. Hoffman, M. & Dargaud, Y. (2012) Mechanisms and monitoring of bypassing agent activity. Journal of Thrombosis and Haemostasis, 10, 1478–1485. Khadzhynov, D., Wagner, F., Formella, S., Wiegert, E., Moschetti, V., Slowinski, T., Neumayer, H.H., Liesenfeld, K.H., Lehr, T., Hartter, S., Friedman, J., Peters, H. & Clemens, A. (2013) Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thrombosis and Haemostasis, 109, 596–605. Lillo-Le Louet, A., Wolf, M., Soufir, L., Galbois, A., Dumenil, A.S., Offenstadt, G. & Samama, M.M. (2012) Life-threatening bleeding in four patients with an unusual excessive response to
dabigatran: implications for emergency surgery and resuscitation. Thrombosis and Haemostasis, 108, 583–585. Majeed, A. & Schulman, S. (2013) Bleeding and antidotes in new oral anticoagulants. Best Pract Res Clin Haematol, 26, 191–202. van Ryn, J., Schurer, J., Kink-Eiband, M. & Clemens, A. (2011) The successful reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of anticoagulation. Blood (ASH Annual Meeting Abstracts), 118, 2316. Schiele, F., van Ryn, J., Canada, K., Newsome, C., Sepulveda, E., Park, J., Nar, H. & Litzenburger, T. (2013) A specific antidote for dabigatran: functional and structural characterization. Blood, 121, 3554–3562.
ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2013, 164, 296–310
Activated prothrombin complex concentrate for dabigatran-associated bleeding subdural haematoma with associated midline shift (Fig 2). The last dose of dabigatran, 110 mg, was 2 d before transfer to our hospital. On admission the thrombin time (TT) was 127 s (normal range 20–30 s), activated partial thromboplastin time (aPTT) was 46 s (normal 22–35 s), prothrombin time – international normalized ratio (INR) was 12, dabigatran concentration (with Hemoclot) was 50 ng/ml, and creatinine 135 lmol/l with calculated creatinine clearance of 45 ml/min. The neurosurgeon elected to defer haematoma drainage until dabigatran had been eliminated. The patient received 4600 units (50 units/kg) of aPCC, whereafter the weakness improved without immediate change in the coagulation profile. The thrombin time normalized 3 d later and he underwent uneventful craniotomy with evacuation of 100 ml of blood. Repeat imaging demonstrated resolution of the bleed and he was discharged home the next day. At 1month follow-up, there was complete resolution of the weakness. An 81-year-old female (Hamilton 2) with atrial fibrillation and hypertension woke up in the morning, 12 h after her last dabigatran dose (110 mg), and felt normal but 1 h later she fell off the toilet and was disoriented, unsteady and had right-sided weakness and slurred speech. When the paramedics arrived, 20 min later, her blood pressure was 196/100. CT, 70 min after onset showed acute intra-axial haemorrhage
A humanized antibody fragment to reverse the oral thrombin inhibitor dabigatran is currently under development (Schiele et al, 2013). The absence of a specific reversal agent has caused apprehension over the use of this anticoagulant (Cotton et al, 2011). Prothrombin complex concentrate (PCC) and activated factor VII seemed ineffective in recently reported cases (Lillo-Le Louet et al, 2012), and animal models and ex vivo studies have provided conflicting results Majeed & Schulman, 2013). Although dabigatran has a low degree of binding to plasma proteins and is dialyzable (Khadzhynov et al, 2013), it may take many hours to eliminate this drug from the circulation. We treated four patients with potentially life-threatening dabigatran-associated bleeding with activated PCC (FEIBA, Baxter AG, Vienna, Austria), two in Hamilton, Ontario and two in Edmonton, Alberta. The laboratory and transfusion data are shown in Fig 1. Creatinine clearance was estimated with the Cockroft-Gault formula. An 84-year-old male (Hamilton 1) with a medical history of atrial fibrillation, hypertension and chronic renal insufficiency was urgently referred to our tertiary care hospital with subdural haematoma. He had fallen at home 1 month earlier and, at the time of presentation, had a 3-day history of headache and progressive left sided weakness. Computed tomography (CT) showed acute on chronic right parietal
160
Hamilton 1 140 aPTT or TT, s
aPTT or TT, s
aPTT TT
120
Hamilton 2
140
100 80 60 40 20
aPTT TT
120 100 80 60 40 20
0
0
0
24
48
72
96
120
0
140
Edmonton 1
aPTT or TT, s
120 100 80 60 40 20
72 96 120 144
120
Edmonton 2
100 80 60 40 20 0
0 0
24
48
72
96
120 144 168 192
Hours after last dose dabigatran
308
aPTT TT Hb
140 aPTT or TT, s; Hb, g/l
aPTT TT Hgb
24 48
Hours after last dose of dabigatran
Hours after last dose dabigatran
0
24
48
72
96 120 144 168
Hours (est.) after last dose dabigatran
Fig 1. Evolution of activated partial thromboplastin time (aPTT), thrombin time (TT), haemoglobin concentration (Hb; for the cases with external blood loss) in relation to the last dose of dabigatran. Symbols with an attached upward arrow indicate ‘more than the upper limit of the analysed range’. A blue downward arrow indicates infusion of activated prothrombin complex concentrate. Red downward arrows indicate red cell transfusions.
ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2013, 164, 296–310
Correspondence
Fig 2. Computed tomography scan showing 35 cm right parietal subdural haematoma with 13 mm of midline shift, compression of the right lateral ventricle and mild uncal herniation.
in the left basal ganglia, 18 9 23 9 33 cm with mild perilesional oedema and chronic microangiopathy. Her creatinine was 84 lmol/l, corresponding to a calculated creatinine clearance of 43 ml/min, aPTT was 48 s (normal 22–35 s) and TT >150 s (normal 20–30 s). She received aPCC 2500 units (42 units/kg) starting 4 h after onset. Repeat imaging after 3 d showed a mild increase in the haematoma (22 9 30 9 38 cm). There was no further progression of her symptoms; her speech normalized on the day of admission but her motor function required 2 months of rehabilitation. At follow-up, 13 weeks after the event, she had normal mobility and strength but slight numbness on her right side. An 85-year-old female (Edmonton 1) with atrial fibrillation, hypertension, dyslipidaemia, chronic kidney disease and previous myocardial infarction required insertion of a dual-chamber pacemaker due to sinus node tachy-bradydysfunction and 7s-pauses. The patient was on aspirin 81 mg. After the insertion, dabigatran was started at 75 mg b.i.d. due to a calculated creatinine clearance of 27 ml/min. The creatinine subsequently increased from 160 to 424 lmol/l, the patient became hypotensive and an echocardiogram demonstrated penetration of a pacemaker lead into the pericardium, where there was a circumferential effusion. The aPTT was 65 s but pericardiocentesis was of vital importance, so 100 units/kg of aPCC was infused, immediately followed by centesis, draining 700 ml of blood. The bleeding ceased but the thrombin time remained unmeasurable for three more days. An 83-year-old female (Edmonton 2) with atrial fibrillation was admitted for upper gastrointestinal bleeding; haemoglobin concentration (Hb) was 99 g/l and creatinine clearance 24 ml/min. Dabigatran, started 1 month earlier at 110 mg b.i.d. (creatinine clearance then 43 ml/min), was withheld but her Hb continued to decrease, to 70 g/l ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2013, 164, 296–310
after 3 d. Upper endoscopy was performed to verify the bleeding, aPCC at a dose of 50 units/kg and 3 units of red cells were administered and the clinical condition stabilized. These cases illustrate how life-threatening dabigatranassociated bleeding might be controlled with aPCC, supported by another case (Dager et al, 2013). These reports are admittedly anecdotal but still of interest whilst awaiting specifically designed clinical studies. The mechanism of action is unclear but might entail boosting the prothrombinase complex on the platelet surface (Hoffman & Dargaud, 2012). Alternatively, high levels of prothrombin increase the velocity of thrombin generation (Hoffman & Dargaud, 2012). aPCC does not remove dabigatran, explaining the unchanged thrombin time. With the retrospective nature of data collection, our laboratory data are limited. Discrepant haemostatic and laboratory results were also seen in animal models (van Ryn et al, 2011), and in healthy volunteers receiving dabigatran, aPCC corrected all parameters of thrombin generation (Majeed & Schulman, 2013). In a study with another thrombin inhibitor, melagatran, aPCC reduced blood loss in the rat tail bleeding model (Elg et al, 2001a). In comparison with other haemostatic agents, aPCC seemed to be the most effective for shortening the bleeding time in animals exposed to high doses of melagatran (Elg et al, 2001b). Doses of aPCC corresponding to 80–160 units/kg corrected some of the thrombin generation parameters to supranormal levels in the above-mentioned ex vivo study ((Majeed & Schulman, 2013) and therefore it might be prudent to attempt reversal in clinical situations with only 50 units/kg, which is at the lower end of the dose range used in haemophilia with inhibitors. Further studies are required to confirm the benefits and identify harms of aPCC in dabigatran-associated major bleeding.
Author contributions BR, SN, MA and SG managed the cases and provided the data, SS and JKG wrote the manuscript, all co-authors read critically and revised the manuscript.
Competing interests SS has received honoraria from Boehringer Ingelheim for work in study committees. Sam Schulman1 Bruce Ritchie2 Jennifer K. Goy1 Susan Nahirniak3 Mohammad Almutawa4 Shari Ghanny1 1
Department of Medicine, McMaster University, Hamilton, ON,
2
Department of Medicine, University of Alberta, 3Department of
309
Correspondence Laboratory Medicine and Pathology, University of Alberta, and
Keywords: dabigatran, bleeding activated prothrombin complex
4
concentrate
Division of Cardiology, Mazankowski Heart Institute, University of
Alberta, Edmonton, AB, Canada E-mail: [email protected]
First published online 23 October 2013 doi: 10.1111/bjh.12620
References Cotton, B.A., McCarthy, J.J. & Holcomb, J.B. (2011) Acutely injured patients on dabigatran. New England Journal of Medicine, 365, 2039–2040. Dager, W.E., Gosselin, R.C. & Roberts, A.J. (2013) Reversing dabigatran in a life-threatening bleed occurring during cardiac ablation with factor eight inhibitor bypassing activity. Critical Care Medicine, 41, e42–e46. Elg, M., Carlsson, S. & Gustafsson, D. (2001a) Effects of activated prothrombin complex concentrate or recombinant factor VIIa on bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor. Thrombosis Research, 101, 145–157. Elg, M., Carlsson, S. & Gustafsson, D. (2001b) Effects of agents, used to treat bleeding disorders,
310
on bleeding time prolonged by a very high dose of a direct thrombin inhibitor in anesthesized rats and rabbits. Thrombosis Research, 101, 159–170. Hoffman, M. & Dargaud, Y. (2012) Mechanisms and monitoring of bypassing agent activity. Journal of Thrombosis and Haemostasis, 10, 1478–1485. Khadzhynov, D., Wagner, F., Formella, S., Wiegert, E., Moschetti, V., Slowinski, T., Neumayer, H.H., Liesenfeld, K.H., Lehr, T., Hartter, S., Friedman, J., Peters, H. & Clemens, A. (2013) Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thrombosis and Haemostasis, 109, 596–605. Lillo-Le Louet, A., Wolf, M., Soufir, L., Galbois, A., Dumenil, A.S., Offenstadt, G. & Samama, M.M. (2012) Life-threatening bleeding in four patients with an unusual excessive response to
dabigatran: implications for emergency surgery and resuscitation. Thrombosis and Haemostasis, 108, 583–585. Majeed, A. & Schulman, S. (2013) Bleeding and antidotes in new oral anticoagulants. Best Pract Res Clin Haematol, 26, 191–202. van Ryn, J., Schurer, J., Kink-Eiband, M. & Clemens, A. (2011) The successful reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of anticoagulation. Blood (ASH Annual Meeting Abstracts), 118, 2316. Schiele, F., van Ryn, J., Canada, K., Newsome, C., Sepulveda, E., Park, J., Nar, H. & Litzenburger, T. (2013) A specific antidote for dabigatran: functional and structural characterization. Blood, 121, 3554–3562.
ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2013, 164, 296–310
