Thrombosis Research 135 (2015) 568–570
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Letter to the Editors-in-Chief Rivaroxaban as anticoagulant therapy in short bowel syndrome. Report of three cases
Dear Editors, Short bowel syndrome is defined as a physical or functional loss of function of the small intestine resulting in a malabsorptive disorder. The condition is often a result of extensive intestinal resection e.g. after mesenteric vascular events or complications from previous abdominal surgery. Patients with short bowel syndrome receive nutritional treatment through central catheters placed where the superior caval vein joins the right atrium, but a common complication to central catheters is central vein thrombosis. Furthermore, patients with short bowel syndrome are often multi-diseased patients with a need for prophylactic anticoagulation therapy, either because of previous thrombosis or because of atrial fibrillation or heart valve prosthesis. Very often, these patients have only 30 cm or less of their small bowel left. Therefore, these patients have problems, not only with the absorption of nutrients, but also with oral drug therapy. Anticoagulation therapy with warfarin is especially challenging in these patients, and vitamin K deficiency may appear in patients with short bowel disease [1]. In this presentation of three cases, we show how warfarin has been replaced with a non-vitamin K antagonist oral anticoagulant, the factor Xa inhibitor, rivaroxaban. Study Cases The patients were selected because of their need for antithrombotic treatment and previous problems controlling INR in relation to their treatment with Warfarin. None of the case patients received LMWH before inclusion in this study. Since these measurements were part of the treatment, approval from the Ethical Committee was not needed according to Danish law. Case 1 In 2011, a 65-year-old man, weight 73 kg with no previous diseases was admitted with severe abdominal pain. After three laparotomies showing ischemic intestine leading to intestinal resections, he ended up with 30 cm of small intestine directly anastomosed to the ascending colon. This incident was considered secondary to thrombosis of the superior mesenteric and portal veins. The patient was transferred to our special intestinal failure unit, and home parenteral nutrition through a Hickman catheter was established. After one year, he was no longer in need of parenteral nutrition. To prevent new mesenteric vein thrombosis, he was commenced with warfarin therapy. Due to difficulties in achieving sufficient time in therapeutic range (TTR) with warfarin anticoagulation, we decided to switch to treatment with rivaroxaban 20 mg once daily (OD).
http://dx.doi.org/10.1016/j.thromres.2015.01.005 0049-3848/© 2015 Elsevier Ltd. All rights reserved.
Case 2 A 59-year old woman, weight 41 kg. In 1998, she had a severe postERCP (Endoscopic Retrograde Cholangio Pancreatography) necrotizing pancreatitis, which was treated with several necrosectomies. She was left with an intact intestine but with severe dysmotility, and therefore she started parenteral nutrition. In 2006, a major intestinal resection was performed due to extensive intra abdominal adhesions. She was left with 75 cm of the jejunum anastomosed to the distal 10 cm of the sigmoid colon. In 2008, warfarin therapy was started due to catheterassociated thrombosis of the superior caval vein. In 2013, we decided, due to insufficient TTR, to change her anticoagulant treatment to rivaroxaban 20 mg OD. Case 3 A 47-year old man, weight 71 kg with Crohn’s disease since 1995. In 2006, he was admitted septicaemic and underwent extensive intestinal resections. He was left with 100 cm of the jejunum ending in a jejunostomi, and 60 cm of the left colon. He was thereafter dependent on intravenous nutritional support. In 2013, the intestinal continuity was established (100 cm jejunum to 60 cm left colon). He managed without intravenous nutritional support until spring 2014, but in May 2014, he developed a deep venous thrombosis of the right leg extending from the lower limb veins up to the external iliac vein. Warfarin therapy was started, but because of poor anticoagulation control, he was switched to treatment with rivaroxaban 20 mg OD. Assessment of Pharmacokinetics In all three cases described, we measured the patients’ plasma concentrations to document that the drug was absorbed and the measured values were in accordance with the levels found in clinical studies indicating sufficient anticoagulation [2]. Plasma levels of rivaroxaban were measured the first day of treatment within the time frame where the maximal concentration was expected, i.e. within 2-4 h. According to Mueck et al. [2] rivaroxaban do not accumulate to a relevant extent after multiple dosing. Blood samples were centrifuged at 2200 g for 15 min. at 20 °C and analysis was performed immediately after the last blood sampling. Rivaroxaban was quantified by a chromogenic anti-factor Xa method (COAMATIC® Heparin, Chromogenix, 20128 Milano, Italy) calibrated with rivaroxaban calibrators from Technoclone GmbH (1230 Vienna, Austria). The maximum plasma concentrations (Cmax) being reached 2–4 h after a single dose of rivaroxaban, for all three patients, were within the 90 % central interval for concentrations found for patients receiving 20 mg of rivaroxaban OD in the initial clinical trial (Fig. 1) [3]. The patient in case 2 reported severe side effects, mainly nausea, and treatment was stopped. The other patients continued treatment and there have been no thrombotic complications in this time period (six and twelve months respectively). Until recently, warfarin has been the only effective oral anticoagulant therapy in patients in need for thrombosis prophylaxis. This treatment has, however, some limitations because of its need for
Letter to the Editors-in-Chief
Fig. 1. The patients’ plasma concentrations were measured values were in accordance with the levels found in clinical studies indicating sufficient anticoagulation.
tailored individual dosing based on careful monitoring of the international normalized ratio (INR). The quality of warfarin control being directly related to survival is difficult to obtain at a satisfying level in patients with short bowel syndrome [4]. Furthermore, the absorption is affected by various types of drugs and vitamin K-containing foods [5]. In other settings, some patients receive LMWH as anticoagulant treatment often for short or medium term treatment. It has the drawback of being administered subcutaneously and associated inappropriate side effects. We usually do not advise this option for longterm treatment in our patients. In all three cases presented, short bowel syndrome resulted in difficulties in obtaining sufficient TTR in patients on warfarin treatment. Thus, an alternative oral anticoagulant was needed, preferably a drug that was absorbed in the stomach or proximal small intestine. Rivaroxaban met these requirements, and therefore these patients were subscribed 20 mg rivaroxaban OD. Rivaroxaban is a direct inhibitor of free and clot-bound Factor Xa (FXa), and indirectly inhibits the generation of thrombin [6,7]. It is absorbed primarily from the proximal intestinal lumen with a bioavailability of approximately 80-90%. The absorption sites have been investigated in phase I experiments in healthy subjects, which indicated that 30 % of the absorption occurs in the stomach and duodenum. In the proximal ileum, approximately 50 % has been absorbed and the rest are absorbed in the distal ileum [7]. In the clinical phase III program, comprising studies in the prevention of deep vein thrombosis following hip and knee surgery, treatment and secondary prevention of venous thromboembolism, and the prevention of stroke and systemic embolism in atrial fibrillation, the pharmacokinetic and pharmacodynamic properties have been measured in rivaroxaban treated patients with different dosing schemes [8]. This allowed for estimation of plasma concentrations in these populations describing the peak- and through levels. Although routine monitoring of treatment with rivaroxaban is not necessary, these plasma concentration intervals make it possible in selected cases to assess patient drug intake and levels [2]. Following the intake of an oral rivaroxaban dose, which at 20 mg must be in combination with food (not fasting), maximum concentrations can be detected after 2-4 hours [6]. For patients receiving 20 mg OD, a median concentration of 223 μg/l with 5 and 95 % percentiles of 160 and 360 μg/l respectively, were found in the initial clinical study [3], and later studies found similar intervals with 5 % percentiles of 180-190 μg/l and 95 % percentiles of 340-420 μg/l [2]. Since proper therapeutic levels have not been established these provide an indication of relevant levels. Various techniques have been used for quantification of rivaroxaban in plasma but the chromogenic anti-factor Xa method is recognized as a reliable and
569
reproducible method [9]. In the initial trials mass spectrometry was used for quantitation but anti-factor Xa measurement is in excellent agreement with this technique [9]. The clinical features of the short bowel syndrome vary depending on the extent of lost intestine and the ability of the remaining intestine to compensate. Extensive resection can result in malabsorption of lipid nutrients, electrolytes, water and orally administered medical therapy, the latter resulting in difficulties in drug administration in this group of patients [10]. This reveals the necessity for drugs with proximal absorption in the gastrointestinal tract, especially when the drug has a narrow therapeutic level or is vital for the patient. The proximal absorption makes rivaroxaban well suited for this group of patients with short bowel syndrome having a need for anticoagulant therapy to prevention of future thrombotic complications. As all of our patients after intake of 20 mg rivaroxaban had plasma concentrations within the 90 % central interval found in clinical studies, we conclude that rivaroxaban could turn out to be an alternative oral anticoagulant in patients with short bowel syndrome. However, to prove efficacy and safety a randomized controlled trial is warranted. Addendum L.D. Christensen, L.Vinter-Jensen and T.B. Larsen designed the study, collected and analyzed the data, and wrote the manuscript. S.R. Kristensen performed and interpreted the laboratory analyses and reviewed and revised the manuscript. H.H. Rasmussen reviewed the manuscript and guided the project. All of the above mentioned authors have contributed to the design, interpretation of the data as well as drafting of the manuscript. All authors have approved the manuscript in its present form. Funding Sources None. Disclosure of Conflict of Interests Associate professor Larsen has served as an investigator for Janssen Scientific Affairs, LLC and Boehringer Ingelheim, and has been on the speaker bureaus for Bayer, BMS/Pfizer, Roche Diagnostics, Boehringer Ingelheim and Takeda Pharma. Other authors – none declared. References [1] Krzyzanowska P, Ksiazyk J, Kocielinska-Klos M, Banas E, Kaleta M, Popinska K, et al. Vitamin K status in patients with short bowel syndrome. Clin Nutr Dec 2012;31(6): 1015–7. [2] Mueck W, Stampfuss J, Kubitza D, Becka M. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet Jan 2014;53(1):1–16. [3] Mueck W, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK, et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost Sep 2008;100(3):453–61. [4] Morgan CL, McEwan P, Tukiendorf A, Robinson PA, Clemens A, Plumb JM. Warfarin treatment in patients with atrial fibrillation: observing outcomes associated with varying levels of INR control. Thromb Res May 2009;124(1):37–41. [5] Breckenridge A, Orme M, Wesseling H, Lewis RJ, Gibbons R. Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man. Clin Pharmacol Ther Apr 1974;15(4):424–30. [6] Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov Jan 2011;10(1):61–75. [7] Gerotziafas GT, Elalamy I, Depasse F, Perzborn E, Samama MM. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban. J Thromb Haemost Apr 2007;5(4):886–8. [8] Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet Jul 5 2008;372(9632):31–9.
570
Letter to the Editors-in-Chief
[9] Asmis LM, Alberio L, Angelillo-Scherrer A, Korte W, Mendez A, Reber G, et al. Rivaroxaban: Quantification by anti-FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories. Thromb Res Apr 2012;129(4):492–8. [10] Jeppesen PB. Spectrum of short bowel syndrome in adults: intestinal insufficiency to intestinal failure. JPEN J Parenter Enteral Nutr May 2014;38(1 Suppl.):8S–13S.
Line Dahlstrøm Christensen⁎ Lars Vinter-Jensen Henrik Højgaard Rasmussen Centre for Nutrition and Bowel Disease, Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark ⁎Corresponding author at: Centre for Nutrition and Bowel Disease, Department of Gastroenterology, Aalborg University Hospital, Hobrovej, DK-9100 Aalborg, Denmark. E-mail address: [email protected].
Søren Risom Kristensen Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark Torben Bjerregaard Larsen Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark 5 October 2014
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Letter to the Editors-in-Chief Rivaroxaban as anticoagulant therapy in short bowel syndrome. Report of three cases
Dear Editors, Short bowel syndrome is defined as a physical or functional loss of function of the small intestine resulting in a malabsorptive disorder. The condition is often a result of extensive intestinal resection e.g. after mesenteric vascular events or complications from previous abdominal surgery. Patients with short bowel syndrome receive nutritional treatment through central catheters placed where the superior caval vein joins the right atrium, but a common complication to central catheters is central vein thrombosis. Furthermore, patients with short bowel syndrome are often multi-diseased patients with a need for prophylactic anticoagulation therapy, either because of previous thrombosis or because of atrial fibrillation or heart valve prosthesis. Very often, these patients have only 30 cm or less of their small bowel left. Therefore, these patients have problems, not only with the absorption of nutrients, but also with oral drug therapy. Anticoagulation therapy with warfarin is especially challenging in these patients, and vitamin K deficiency may appear in patients with short bowel disease [1]. In this presentation of three cases, we show how warfarin has been replaced with a non-vitamin K antagonist oral anticoagulant, the factor Xa inhibitor, rivaroxaban. Study Cases The patients were selected because of their need for antithrombotic treatment and previous problems controlling INR in relation to their treatment with Warfarin. None of the case patients received LMWH before inclusion in this study. Since these measurements were part of the treatment, approval from the Ethical Committee was not needed according to Danish law. Case 1 In 2011, a 65-year-old man, weight 73 kg with no previous diseases was admitted with severe abdominal pain. After three laparotomies showing ischemic intestine leading to intestinal resections, he ended up with 30 cm of small intestine directly anastomosed to the ascending colon. This incident was considered secondary to thrombosis of the superior mesenteric and portal veins. The patient was transferred to our special intestinal failure unit, and home parenteral nutrition through a Hickman catheter was established. After one year, he was no longer in need of parenteral nutrition. To prevent new mesenteric vein thrombosis, he was commenced with warfarin therapy. Due to difficulties in achieving sufficient time in therapeutic range (TTR) with warfarin anticoagulation, we decided to switch to treatment with rivaroxaban 20 mg once daily (OD).
http://dx.doi.org/10.1016/j.thromres.2015.01.005 0049-3848/© 2015 Elsevier Ltd. All rights reserved.
Case 2 A 59-year old woman, weight 41 kg. In 1998, she had a severe postERCP (Endoscopic Retrograde Cholangio Pancreatography) necrotizing pancreatitis, which was treated with several necrosectomies. She was left with an intact intestine but with severe dysmotility, and therefore she started parenteral nutrition. In 2006, a major intestinal resection was performed due to extensive intra abdominal adhesions. She was left with 75 cm of the jejunum anastomosed to the distal 10 cm of the sigmoid colon. In 2008, warfarin therapy was started due to catheterassociated thrombosis of the superior caval vein. In 2013, we decided, due to insufficient TTR, to change her anticoagulant treatment to rivaroxaban 20 mg OD. Case 3 A 47-year old man, weight 71 kg with Crohn’s disease since 1995. In 2006, he was admitted septicaemic and underwent extensive intestinal resections. He was left with 100 cm of the jejunum ending in a jejunostomi, and 60 cm of the left colon. He was thereafter dependent on intravenous nutritional support. In 2013, the intestinal continuity was established (100 cm jejunum to 60 cm left colon). He managed without intravenous nutritional support until spring 2014, but in May 2014, he developed a deep venous thrombosis of the right leg extending from the lower limb veins up to the external iliac vein. Warfarin therapy was started, but because of poor anticoagulation control, he was switched to treatment with rivaroxaban 20 mg OD. Assessment of Pharmacokinetics In all three cases described, we measured the patients’ plasma concentrations to document that the drug was absorbed and the measured values were in accordance with the levels found in clinical studies indicating sufficient anticoagulation [2]. Plasma levels of rivaroxaban were measured the first day of treatment within the time frame where the maximal concentration was expected, i.e. within 2-4 h. According to Mueck et al. [2] rivaroxaban do not accumulate to a relevant extent after multiple dosing. Blood samples were centrifuged at 2200 g for 15 min. at 20 °C and analysis was performed immediately after the last blood sampling. Rivaroxaban was quantified by a chromogenic anti-factor Xa method (COAMATIC® Heparin, Chromogenix, 20128 Milano, Italy) calibrated with rivaroxaban calibrators from Technoclone GmbH (1230 Vienna, Austria). The maximum plasma concentrations (Cmax) being reached 2–4 h after a single dose of rivaroxaban, for all three patients, were within the 90 % central interval for concentrations found for patients receiving 20 mg of rivaroxaban OD in the initial clinical trial (Fig. 1) [3]. The patient in case 2 reported severe side effects, mainly nausea, and treatment was stopped. The other patients continued treatment and there have been no thrombotic complications in this time period (six and twelve months respectively). Until recently, warfarin has been the only effective oral anticoagulant therapy in patients in need for thrombosis prophylaxis. This treatment has, however, some limitations because of its need for
Letter to the Editors-in-Chief
Fig. 1. The patients’ plasma concentrations were measured values were in accordance with the levels found in clinical studies indicating sufficient anticoagulation.
tailored individual dosing based on careful monitoring of the international normalized ratio (INR). The quality of warfarin control being directly related to survival is difficult to obtain at a satisfying level in patients with short bowel syndrome [4]. Furthermore, the absorption is affected by various types of drugs and vitamin K-containing foods [5]. In other settings, some patients receive LMWH as anticoagulant treatment often for short or medium term treatment. It has the drawback of being administered subcutaneously and associated inappropriate side effects. We usually do not advise this option for longterm treatment in our patients. In all three cases presented, short bowel syndrome resulted in difficulties in obtaining sufficient TTR in patients on warfarin treatment. Thus, an alternative oral anticoagulant was needed, preferably a drug that was absorbed in the stomach or proximal small intestine. Rivaroxaban met these requirements, and therefore these patients were subscribed 20 mg rivaroxaban OD. Rivaroxaban is a direct inhibitor of free and clot-bound Factor Xa (FXa), and indirectly inhibits the generation of thrombin [6,7]. It is absorbed primarily from the proximal intestinal lumen with a bioavailability of approximately 80-90%. The absorption sites have been investigated in phase I experiments in healthy subjects, which indicated that 30 % of the absorption occurs in the stomach and duodenum. In the proximal ileum, approximately 50 % has been absorbed and the rest are absorbed in the distal ileum [7]. In the clinical phase III program, comprising studies in the prevention of deep vein thrombosis following hip and knee surgery, treatment and secondary prevention of venous thromboembolism, and the prevention of stroke and systemic embolism in atrial fibrillation, the pharmacokinetic and pharmacodynamic properties have been measured in rivaroxaban treated patients with different dosing schemes [8]. This allowed for estimation of plasma concentrations in these populations describing the peak- and through levels. Although routine monitoring of treatment with rivaroxaban is not necessary, these plasma concentration intervals make it possible in selected cases to assess patient drug intake and levels [2]. Following the intake of an oral rivaroxaban dose, which at 20 mg must be in combination with food (not fasting), maximum concentrations can be detected after 2-4 hours [6]. For patients receiving 20 mg OD, a median concentration of 223 μg/l with 5 and 95 % percentiles of 160 and 360 μg/l respectively, were found in the initial clinical study [3], and later studies found similar intervals with 5 % percentiles of 180-190 μg/l and 95 % percentiles of 340-420 μg/l [2]. Since proper therapeutic levels have not been established these provide an indication of relevant levels. Various techniques have been used for quantification of rivaroxaban in plasma but the chromogenic anti-factor Xa method is recognized as a reliable and
569
reproducible method [9]. In the initial trials mass spectrometry was used for quantitation but anti-factor Xa measurement is in excellent agreement with this technique [9]. The clinical features of the short bowel syndrome vary depending on the extent of lost intestine and the ability of the remaining intestine to compensate. Extensive resection can result in malabsorption of lipid nutrients, electrolytes, water and orally administered medical therapy, the latter resulting in difficulties in drug administration in this group of patients [10]. This reveals the necessity for drugs with proximal absorption in the gastrointestinal tract, especially when the drug has a narrow therapeutic level or is vital for the patient. The proximal absorption makes rivaroxaban well suited for this group of patients with short bowel syndrome having a need for anticoagulant therapy to prevention of future thrombotic complications. As all of our patients after intake of 20 mg rivaroxaban had plasma concentrations within the 90 % central interval found in clinical studies, we conclude that rivaroxaban could turn out to be an alternative oral anticoagulant in patients with short bowel syndrome. However, to prove efficacy and safety a randomized controlled trial is warranted. Addendum L.D. Christensen, L.Vinter-Jensen and T.B. Larsen designed the study, collected and analyzed the data, and wrote the manuscript. S.R. Kristensen performed and interpreted the laboratory analyses and reviewed and revised the manuscript. H.H. Rasmussen reviewed the manuscript and guided the project. All of the above mentioned authors have contributed to the design, interpretation of the data as well as drafting of the manuscript. All authors have approved the manuscript in its present form. Funding Sources None. Disclosure of Conflict of Interests Associate professor Larsen has served as an investigator for Janssen Scientific Affairs, LLC and Boehringer Ingelheim, and has been on the speaker bureaus for Bayer, BMS/Pfizer, Roche Diagnostics, Boehringer Ingelheim and Takeda Pharma. Other authors – none declared. References [1] Krzyzanowska P, Ksiazyk J, Kocielinska-Klos M, Banas E, Kaleta M, Popinska K, et al. Vitamin K status in patients with short bowel syndrome. Clin Nutr Dec 2012;31(6): 1015–7. [2] Mueck W, Stampfuss J, Kubitza D, Becka M. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet Jan 2014;53(1):1–16. [3] Mueck W, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK, et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost Sep 2008;100(3):453–61. [4] Morgan CL, McEwan P, Tukiendorf A, Robinson PA, Clemens A, Plumb JM. Warfarin treatment in patients with atrial fibrillation: observing outcomes associated with varying levels of INR control. Thromb Res May 2009;124(1):37–41. [5] Breckenridge A, Orme M, Wesseling H, Lewis RJ, Gibbons R. Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man. Clin Pharmacol Ther Apr 1974;15(4):424–30. [6] Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov Jan 2011;10(1):61–75. [7] Gerotziafas GT, Elalamy I, Depasse F, Perzborn E, Samama MM. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban. J Thromb Haemost Apr 2007;5(4):886–8. [8] Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet Jul 5 2008;372(9632):31–9.
570
Letter to the Editors-in-Chief
[9] Asmis LM, Alberio L, Angelillo-Scherrer A, Korte W, Mendez A, Reber G, et al. Rivaroxaban: Quantification by anti-FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories. Thromb Res Apr 2012;129(4):492–8. [10] Jeppesen PB. Spectrum of short bowel syndrome in adults: intestinal insufficiency to intestinal failure. JPEN J Parenter Enteral Nutr May 2014;38(1 Suppl.):8S–13S.
Line Dahlstrøm Christensen⁎ Lars Vinter-Jensen Henrik Højgaard Rasmussen Centre for Nutrition and Bowel Disease, Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark ⁎Corresponding author at: Centre for Nutrition and Bowel Disease, Department of Gastroenterology, Aalborg University Hospital, Hobrovej, DK-9100 Aalborg, Denmark. E-mail address: [email protected].
Søren Risom Kristensen Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark Torben Bjerregaard Larsen Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark 5 October 2014
