letter to the editor Wien Klin Wochenschr (2014) 126:62–63 DOI 10.1007/s00508-013-0454-8
Wiener klinische Wochenschrift
The Central European Journal of Medicine
Gastrointestinal bleeding associated with dabigatran in a patient with panhypopituitarism Fahri Gunes · Mehmet Asik · Ahmet Temiz · Emine Binnetoglu · Hacer Sen · Ogun I˙rem Bilen · Erdem Akbal · Gurhan Adam · Kubilay Ukinc
Received: 15 April 2013 / Accepted: 16 October 2013 / Published online: 16 November 2013 © Springer-Verlag Wien 2013
Dear editor Dabigatran is a direct thrombin inhibitor that is used to reduce the risk of systemic embolism in patients with atrial fibrillation (AF). It does not require international normalised ratio (INR) monitoring during the course of treatment, and this arise from the most important advantage of this drug when compared with coumadin. The main complication of dagibatran is bleeding of the gastrointestinal system [1]. Bleeding diathesis, renal dysfunction, age, and concomitant antiplatelet medications are associated with bleeding complications [2]. Sheehan’s syndrome (SS) is a postpartum pituitary deficiency caused by necrosis of the pituitary gland. It is characterized by varying degrees of anterior pituitary dysfunction. Panhypopituitarism has been associated with bleeding disorders in some previous studies and case reports [3]. However, a relationship of panhypopituitarism and dabigatran associated bleeding has not been reported. F. Gunes, MD () · E. Binnetoglu · H. Sen · O. I˙. Bilen Department of Internal Medicine, Çanakkale Onsekiz Mart University, Çanakkale, Turkey e-mail: [email protected] M. Asik, MD · K. Ukinc Department of Endocrinology, Çanakkale Onsekiz Mart University, Çanakkale, Turkey A. Temiz, MD Department of Cardiology, Çanakkale Onsekiz Mart University, Çanakkale, Turkey E. Akbal, MD Department of Gastroenterology, Çanakkale Onsekiz Mart University, Çanakkale, Turkey G. Adam Department of Radiology, Çanakkale Onsekiz Mart University, Çanakkale, Turkey
This article describes a patient who had dabigatranassociated gastrointestinal bleeding and undiagnosed panhypopituitarism. A 74-year-old female patient was admitted to the emergency department with complaint of weakness and melena for past 3 days. Physical examination revealed that arterial blood pressure was 80/50 mmHg and heart rate was 95/min and arrhythmic. Pale skin and conjunctiva was observed. The patient had no history of abnormal bleeding and did not take any antiplatelet medication. Serious bleeding did not occur preceding the present admission. However, 1 year previously, warfarin 5 mg daily dosage to the patient was started in the department of cardiology because of paroxysmal atrial fibrillation. Coumadin therapy was changed to dabigatran (220 mg/day) 1 month ago because of nonadherence to the INR follow-up. Laboratory values showed hemoglobin (Hb): 3.8 g/dL, mean corpuscular volume: 86 fL, platelet: 418,000 K/mm3, Na: 135 mEq/L, K: 3.8 mEq/L, urea: 42 mg/dL, creatinin: 0.78 mg/dL, prothrombin time (PT): 15.1 s, INR: 1.37, activated partial thromboplastin time (aPTT): 48.3 s, and creatinin clearance: 70.5 mL/min. Firstly, we stopped the dabigatran and transfused 3 units of red blood cells and then Hb increased to 9.2 g/dL. Profound hyponatremia (Na: 119 mEq/L) and progressive lethargy developed on the third day of hospitalization. Evaluated for hyponatremia revealed that, she had adrenal insufficency and central hypothyroidism, with measured levels of adrenocorticotropic hormone: 12.5 pg/ mL, cortisol: 5.99 µg/dL, thyroid stimulating hormone: 2.5 IU/mL (normal range: 0.35–4.94 IU/mL), and free thyroxine: 0.52 ng/dL (normal range: 0.70–1.48 ng/dL). Insulin tolerance test could not be performed because of her old age. A synacthhen stimulation test showed that 30 and 60th min cortisol levels were 9.48 µg/dl and 12.72 µg/dl, respectively. Also, other anterior pituitary hormones were consistent with panhypopituitarism, with measured follicle-stimulating hormone: 0.6 mIU/
62 Gastrointestinal bleeding associated with dabigatran in a patient with panhypopituitarism
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letter to the editor
mL (normal range: 25.8–134.8 mIU/ml for post-menapausal women). The levels of factor VIII and von Willebrand factor were in normal ranges. A pituitary magnetic resonance imaging showed empty sella. Her last pregnancy was 40 years ago and she delivered four babies without bleeding complications. She had breastfed her last baby for 1 year and then her menstrual cycles ceased. The patient did not have head pain or vision loss. IV methylprednisolone 60 mg/daily dosage was started. After 3 days, levothyroxine 50 µg/day dosage was added. The patient’s general condition improved, and serum sodium levels increased to normal values. Hb levels remained stable. PT: 12.3 s, aPTT: 31.5 s, and INR: 1.03 was measured after panhypopituitarism replacement therapy. Upper gastrointestinal endoscopy showed multiple erosions in the antrum, but colonoscopy examination was normal. Dabigatran is a direct thrombin inhibitor that does not require follow-up for anticoagulant response. Recent studies showed that some patients treated with dabigatran may develop major bleeding. In these studies, major bleeding was reported as gastrointestinal system bleeding, pericardial hematoma, subdural hematoma, and epistaxis. Advanced age, renal failure, low body weight, and concomitant use of antiplatelet drugs make patients more prone to bleeding complications who were treated with dabigatran [2]. SS has a very large spectrum of clinical presentations, from fatigue and weakness to severe pituitary insufficency. Whereas, a small patient group with SS may show sudden onset severe panhypopituitarism, most patients have mild disease that makes it unrecognized for a long time. One of the most common symptoms of SS is failure of menstruations following pregnancy. Clinical and laboratory findings of hypothyroidism as part of SS may be silent. Adrenocortical insufficency in SS may be one of the most important outcomes with, hypotension, tiredness, hyponatremia, and adrenal crisis. Severe hyponatremia was reported in approximately 50 % of patients, 16 years after the onset of SS [4]. Hematologic abnormalities in SS include normocytic normochromic anemia, pancytopenia and acquired factor VIII and von Willebrand factor deficiency [3]. Anemia may result from a lack of anterior pituitary hormones. A relationship was found in patients with pancytopenia to
13
hypocellular marrow and the condition improved entirely by cortisol and thyroxine replacement [5]. In another study, levels of PT and INR in patients with SS was higher than in healthy controls, but was not significant [6]. In another case report, one patient with MVR and SS took enoxaparin and developed retroperitoneal hematoma as a rare complication [7]. The bleeding tendency in SS may arise from the association with hypothyroidism. Most previous studies proved that there was a bleeding tendency in patients with overt hypothyroidism. Our case did not have risk factors other than advanced age for bleeding due to dabigatran. We suggest that, panhypopituitarism must be kept in mind as a rare cause of bleeding tendency in patients with bleeding complications due to dabigatran treatment. Conflict of interest No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated.
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. Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly. The N Engl J Med. 2012;366(9):864–6. 3. Oliveira MC, Kramer CK, Marroni CP, Leães CG, Viana L, Roithman S, et al. Acquired factor VIII and von Willebrand factor (aFVIII/VWF) deficiency and hypothyroidism in a case with hypopituitarism. Clin Appl Thromb Hemost. 2010;16:107–9. 4. Keles¸timur F. Sheehan’s syndrome. Pituitary. 2003;6:181–8. 5. Laway BA, Mir SA, Bashir MI, Bhat JR, Samoon J, Zargar AH. Prevalence of hematological abnormalities in patients with Sheehan’s syndrome: response to replacement of glucocorticoids and thyroxine. Pituitary. 2011;14:39–43. 6. Gokalp D, Tuzcu A, Bahceci M, Ayyildiz O, Erdemoglu M, Alpagat G. Assessment of bleeding disorders in Sheehan’s syndrome: are bleeding disorders the underlying cause of Sheehan’s syndrome? Platelets. 2011;22:92–7. 7. Karabulut Z, Dogˇan T, Asik M, Ergun T, Lakadamyalı H, Moray G. Spontaneous retroperıtoneal hematoma assocıated wıth enoxaparın: case report. Turkiye Klinikleri J Cardiovasc Sci. 2007;19:186–9.
Gastrointestinal bleeding associated with dabigatran in a patient with panhypopituitarism
63
Wiener klinische Wochenschrift
The Central European Journal of Medicine
Gastrointestinal bleeding associated with dabigatran in a patient with panhypopituitarism Fahri Gunes · Mehmet Asik · Ahmet Temiz · Emine Binnetoglu · Hacer Sen · Ogun I˙rem Bilen · Erdem Akbal · Gurhan Adam · Kubilay Ukinc
Received: 15 April 2013 / Accepted: 16 October 2013 / Published online: 16 November 2013 © Springer-Verlag Wien 2013
Dear editor Dabigatran is a direct thrombin inhibitor that is used to reduce the risk of systemic embolism in patients with atrial fibrillation (AF). It does not require international normalised ratio (INR) monitoring during the course of treatment, and this arise from the most important advantage of this drug when compared with coumadin. The main complication of dagibatran is bleeding of the gastrointestinal system [1]. Bleeding diathesis, renal dysfunction, age, and concomitant antiplatelet medications are associated with bleeding complications [2]. Sheehan’s syndrome (SS) is a postpartum pituitary deficiency caused by necrosis of the pituitary gland. It is characterized by varying degrees of anterior pituitary dysfunction. Panhypopituitarism has been associated with bleeding disorders in some previous studies and case reports [3]. However, a relationship of panhypopituitarism and dabigatran associated bleeding has not been reported. F. Gunes, MD () · E. Binnetoglu · H. Sen · O. I˙. Bilen Department of Internal Medicine, Çanakkale Onsekiz Mart University, Çanakkale, Turkey e-mail: [email protected] M. Asik, MD · K. Ukinc Department of Endocrinology, Çanakkale Onsekiz Mart University, Çanakkale, Turkey A. Temiz, MD Department of Cardiology, Çanakkale Onsekiz Mart University, Çanakkale, Turkey E. Akbal, MD Department of Gastroenterology, Çanakkale Onsekiz Mart University, Çanakkale, Turkey G. Adam Department of Radiology, Çanakkale Onsekiz Mart University, Çanakkale, Turkey
This article describes a patient who had dabigatranassociated gastrointestinal bleeding and undiagnosed panhypopituitarism. A 74-year-old female patient was admitted to the emergency department with complaint of weakness and melena for past 3 days. Physical examination revealed that arterial blood pressure was 80/50 mmHg and heart rate was 95/min and arrhythmic. Pale skin and conjunctiva was observed. The patient had no history of abnormal bleeding and did not take any antiplatelet medication. Serious bleeding did not occur preceding the present admission. However, 1 year previously, warfarin 5 mg daily dosage to the patient was started in the department of cardiology because of paroxysmal atrial fibrillation. Coumadin therapy was changed to dabigatran (220 mg/day) 1 month ago because of nonadherence to the INR follow-up. Laboratory values showed hemoglobin (Hb): 3.8 g/dL, mean corpuscular volume: 86 fL, platelet: 418,000 K/mm3, Na: 135 mEq/L, K: 3.8 mEq/L, urea: 42 mg/dL, creatinin: 0.78 mg/dL, prothrombin time (PT): 15.1 s, INR: 1.37, activated partial thromboplastin time (aPTT): 48.3 s, and creatinin clearance: 70.5 mL/min. Firstly, we stopped the dabigatran and transfused 3 units of red blood cells and then Hb increased to 9.2 g/dL. Profound hyponatremia (Na: 119 mEq/L) and progressive lethargy developed on the third day of hospitalization. Evaluated for hyponatremia revealed that, she had adrenal insufficency and central hypothyroidism, with measured levels of adrenocorticotropic hormone: 12.5 pg/ mL, cortisol: 5.99 µg/dL, thyroid stimulating hormone: 2.5 IU/mL (normal range: 0.35–4.94 IU/mL), and free thyroxine: 0.52 ng/dL (normal range: 0.70–1.48 ng/dL). Insulin tolerance test could not be performed because of her old age. A synacthhen stimulation test showed that 30 and 60th min cortisol levels were 9.48 µg/dl and 12.72 µg/dl, respectively. Also, other anterior pituitary hormones were consistent with panhypopituitarism, with measured follicle-stimulating hormone: 0.6 mIU/
62 Gastrointestinal bleeding associated with dabigatran in a patient with panhypopituitarism
13
letter to the editor
mL (normal range: 25.8–134.8 mIU/ml for post-menapausal women). The levels of factor VIII and von Willebrand factor were in normal ranges. A pituitary magnetic resonance imaging showed empty sella. Her last pregnancy was 40 years ago and she delivered four babies without bleeding complications. She had breastfed her last baby for 1 year and then her menstrual cycles ceased. The patient did not have head pain or vision loss. IV methylprednisolone 60 mg/daily dosage was started. After 3 days, levothyroxine 50 µg/day dosage was added. The patient’s general condition improved, and serum sodium levels increased to normal values. Hb levels remained stable. PT: 12.3 s, aPTT: 31.5 s, and INR: 1.03 was measured after panhypopituitarism replacement therapy. Upper gastrointestinal endoscopy showed multiple erosions in the antrum, but colonoscopy examination was normal. Dabigatran is a direct thrombin inhibitor that does not require follow-up for anticoagulant response. Recent studies showed that some patients treated with dabigatran may develop major bleeding. In these studies, major bleeding was reported as gastrointestinal system bleeding, pericardial hematoma, subdural hematoma, and epistaxis. Advanced age, renal failure, low body weight, and concomitant use of antiplatelet drugs make patients more prone to bleeding complications who were treated with dabigatran [2]. SS has a very large spectrum of clinical presentations, from fatigue and weakness to severe pituitary insufficency. Whereas, a small patient group with SS may show sudden onset severe panhypopituitarism, most patients have mild disease that makes it unrecognized for a long time. One of the most common symptoms of SS is failure of menstruations following pregnancy. Clinical and laboratory findings of hypothyroidism as part of SS may be silent. Adrenocortical insufficency in SS may be one of the most important outcomes with, hypotension, tiredness, hyponatremia, and adrenal crisis. Severe hyponatremia was reported in approximately 50 % of patients, 16 years after the onset of SS [4]. Hematologic abnormalities in SS include normocytic normochromic anemia, pancytopenia and acquired factor VIII and von Willebrand factor deficiency [3]. Anemia may result from a lack of anterior pituitary hormones. A relationship was found in patients with pancytopenia to
13
hypocellular marrow and the condition improved entirely by cortisol and thyroxine replacement [5]. In another study, levels of PT and INR in patients with SS was higher than in healthy controls, but was not significant [6]. In another case report, one patient with MVR and SS took enoxaparin and developed retroperitoneal hematoma as a rare complication [7]. The bleeding tendency in SS may arise from the association with hypothyroidism. Most previous studies proved that there was a bleeding tendency in patients with overt hypothyroidism. Our case did not have risk factors other than advanced age for bleeding due to dabigatran. We suggest that, panhypopituitarism must be kept in mind as a rare cause of bleeding tendency in patients with bleeding complications due to dabigatran treatment. Conflict of interest No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated.
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. Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly. The N Engl J Med. 2012;366(9):864–6. 3. Oliveira MC, Kramer CK, Marroni CP, Leães CG, Viana L, Roithman S, et al. Acquired factor VIII and von Willebrand factor (aFVIII/VWF) deficiency and hypothyroidism in a case with hypopituitarism. Clin Appl Thromb Hemost. 2010;16:107–9. 4. Keles¸timur F. Sheehan’s syndrome. Pituitary. 2003;6:181–8. 5. Laway BA, Mir SA, Bashir MI, Bhat JR, Samoon J, Zargar AH. Prevalence of hematological abnormalities in patients with Sheehan’s syndrome: response to replacement of glucocorticoids and thyroxine. Pituitary. 2011;14:39–43. 6. Gokalp D, Tuzcu A, Bahceci M, Ayyildiz O, Erdemoglu M, Alpagat G. Assessment of bleeding disorders in Sheehan’s syndrome: are bleeding disorders the underlying cause of Sheehan’s syndrome? Platelets. 2011;22:92–7. 7. Karabulut Z, Dogˇan T, Asik M, Ergun T, Lakadamyalı H, Moray G. Spontaneous retroperıtoneal hematoma assocıated wıth enoxaparın: case report. Turkiye Klinikleri J Cardiovasc Sci. 2007;19:186–9.
Gastrointestinal bleeding associated with dabigatran in a patient with panhypopituitarism
63
