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An unusual case of abdominal arterial thrombosis in a young woman using desmopressin
Clinical Biochemistry 45 (2012) 165–167
Contents lists available at SciVerse ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Case Report
An unusual case of abdominal arterial thrombosis in a young woman using desmopressin E.J.M. Schrijver a,⁎, W. Deenik b, H. Chon c, N. Koedam d, A.M.E. Spoelstra-de Man a a
Tergooiziekenhuizen Hilversum, Department of Intensive Care, Van Riebeeckweg 212, 1213 XZ Hilversum, the Netherlands Tergooiziekenhuizen Hilversum, Department of Internal Medicine, Van Riebeeckweg 212, 1213 XZ Hilversum, the Netherlands Tergooiziekenhuizen Hilversum, Department of Clinical Chemistry, Van Riebeeckweg 212, 1213 XZ Hilversum, the Netherlands d Tergooiziekenhuizen Hilversum, Department of Surgery, Van Riebeeckweg 212, 1213 XZ Hilversum, the Netherlands b c
a r t i c l e
i n f o
Article history: Received 2 September 2011 received in revised form 4 November 2011 accepted 17 November 2011 Available online 2 December 2011 Keywords: Desmopressin Arterial thrombosis
a b s t r a c t We report an unusual case of severe abdominal arterial thrombosis in a young woman using oral desmopressin. Only a few cases with cerebrovascular accidents and coronary syndromes have been described so far, which could be attributed to intravenous administration of desmopressin. Because extensive diagnostic and laboratory investigations for (un)common coagulation disorders could not identify an alternative explanation associated with arterial thrombosis, we hypothesise that desmopressin in an oral dose of at least 200 ug once daily must have been sufficient to cause this dramatic vascular complication. Supportive of our hypothesis, we found remarkably high levels of factor VIII activity, Von Willebrand factor (vWF) antigen and vWF ristocetin cofactor activity (268%, 740%, 590% respectively). To the best of the authors' knowledge, this is the first report suggesting a relationship between oral desmopressin use and life-threatening abdominal arterial thrombosis. © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Introduction Desmopressin (1-deamino-8-D-arginine vasopressin, abbreviated DDAVP) is a synthetic vasopressin analogue (V2-receptor agonist). This drug is prescribed for the treatment of diabetes insipidus and nocturnal enuresis, because of its specific antidiuretic effect. Desmopressin stimulates the release of von Willebrand Factor (vWF) from vascular endothelial cells and raises plasma levels of factor VIII, hereby shortening the bleeding time, making it an effective drug to treat patients with coagulation disorders such as haemophilia A and von Willebrand disease (vWD) [1].
Case report A 27-year-old woman presented at the emergency room with a 7-week history of abdominal pain and diarrhoea. She was treated by her general practitioner for a Clostridium difficile-associated diarrhoea with metronidazole 500 mg orally three times daily for 10 days. Her medical history included borderline personality disorder with multiple auto-intoxications requiring hospital admission. Because of nocturnal enuresis, she was prescribed desmopressin 200 ug once daily since approximately 3 months next to aripiprazole, citalopram, alprazolam and topiramate. On physical examination her vital signs were normal. ⁎ Corresponding author. E-mail address: [email protected] (E.J.M. Schrijver).
Abdominal examination revealed decreased bowel sounds with diffuse abdominal pain without muscular defence. Rectal examination was normal. Laboratory results included a sodium level of 132 mmol/L (137–144), a potassium level of 3.3 mmol/L (3.5–5.0), C-reactive protein 180 mg/L (b5.0), leukocyte count of 23.7 × 10 9/L (4.0–11.0) with 10% of band-forms in the differential count, lactate 4.8 mmol/L (b2.0) and a creatinine level of 47 umol/L (50–95). Coagulation tests were not performed in the emergency room. An abdominal CT scan showed an ileus of the small intestine with thickening of the jejunum. Gastroscopy showed severe reflux oesophagitis. She was admitted to hospital for observation. Because of clinical deterioration and an increase in plasma C-reactive protein and lactate, an exploratory laparotomy was performed the day after admission. Unexpectedly, this exploratory laparotomy revealed extensive small bowel ischaemia 30 cm distal to the ligament of Treitz until 50 cm proximal to the ileocoecal valve. Part of the left lobe of the liver appeared necrotic, as well as a part of the spleen. The colon and sigmoid were both well-perfused. The abdomen was temporarily closed to perform a per-operative abdominal contrast-enhanced CT-scan, which showed occlusion of the coeliac trunk, hepatic artery, lineal artery, left gastric artery and superior mesenteric artery (4 cm from its origin) (Fig. 1). A thrombectomy of these arteries was performed and therapeutic doses of unfractionated heparin were infused. Remarkably, thrombosis of the celiac trunk immediately recurred during the procedure, suggestive of a severe coagulation disorder. An aortahepatic bypass was made and the majority of the small bowel was resected, leaving a residual small intestinal length of less than 100 cm.
0009-9120/$ – see front matter © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2011.11.011
166
E.J.M. Schrijver et al. / Clinical Biochemistry 45 (2012) 165–167
Fig. 1. Thrombus in the celiac trunk (CT scan, arterial phase).
A severe coagulation disorder was suspected as the underlying cause of extensive arterial thrombosis in this young woman. A catastrophic antiphospholipid syndrome could not be confirmed: lupus anticoagulant (LAC) antibodies, beta-2 glycoprotein-I (B2GP1) antibodies and anticardiolipin antibodies (ACA) were all negative. Additional testing for coagulation disorders, like factor V Leiden, prothrombin G20210A and Jak-2 V617F gene mutation, showed no abnormalities. Measurements of protein C (normal activity range 75–125%), protein S (normal plasma activity range 70–130%) and antithrombin (AT) III (normal plasma pool activity range 80–120%) in the acute phase of thrombosis all showed decreased activity (42%, 48% and 43% respectively). Homocysteine levels were not measured. Paroxysmal nocturnal haemoglobinuria (PNH) was excluded since flow cytometry of peripheral blood revealed normal CD55/CD59 expression, and positive fluorescent cell labelling of the protein aerolysin (FLAER) rejected the presence of PNH granulocytes. Anti-nuclear antibodies (ANA) and anti-neutrophilic cytoplasmic antibodies (ANCA) were negative. Further results showed remarkable elevations in factor VIII activity, von Willebrand factor antigen (vWF:Ag) and vWF ristocetin cofactor (vWF:RiCo) activity (268%, 740%, 590% respectively). There were no signs of vasculitis, or atherosclerosis on histopathological investigation. Transesophageal echocardiography did not show left atrial thrombus or left ventricular thrombus.
to be as high as observed in our patient. For example, in endotoxininduced systemic inflammation, increased vWF:Ag of up to 259 ± 16% of the baseline value has been detected [6], whereas vWF:Ag was 740% in our case. Second, arterial thrombotic events associated with the use of desmopressin have been reported before. A few cases with cerebrovascular accidents and coronary syndromes have been described which could be attributed to the intravenous administration of desmopressin [7,8]. Noteworthy, our patient used oral desmopressin. However, the pharmacodynamic effects of oral desmopressin (200 ug) have been shown to be similar in magnitude to those after an intravenous dose (2 ug) at night and during the first 6 hours after daytime administration in healthy men aged 55–70 years, despite low bioavailability of orally administered desmopressin (0.08%) [9]. Third, another argument supporting our hypothesis that desmopressin played an important role in the pathophysiology of arterial thrombosis is that our patient was hyponatriemic on admission. Desmopressin binds to V2 receptors in renal collecting ducts, hereby increasing the reabsorption of water, leading to hyponatremia from simple overhydration. Although mild, and in this case other causes may have contributed to this patient's hyponatremia (e.g. diarrhoea in combination with low intake accompanying abdominal pain), numerous reports exist on cases of mild to moderate and even severe desmopressin-induced hyponatremia in healthy adults and individuals with von Willebrand's disease (vWD) [10,11]. Quantified plasma desmopressin concentrations at time of admission could have confirmed our hypothesis. Unfortunately, no direct sample suitable to measure plasma desmopressin levels was collected at that time. Considering other causes of arterial thrombosis, different infectious pathogens have been suggested as responsible agents for thrombotic disorders by the induction of antiphospholipid antibodies, the presence of ACA and/or LAC [12,13]. In this case, the patient was diagnosed and treated for a C. difficile infection by her general practitioner before hospital admission. However, since above-mentioned antibodies were all negative, we reject a possible role for C. difficileinduced pseudomembranous colitis as a trigger for the thrombosis in this patient [14]. Hereditary thrombophilia mostly triggers venous thrombotic events, but there are reports on arterial thrombosis secondary to reduced protein S and protein C activity [15]. Protein C, protein S and ATIII plasma activity were all in the lower range in our patient, most likely due to consumption coagulopathy. Notably, the tests in our patient were performed during the acute phase of thrombosis, which is unreliable [16–18]. In addition, a still unknown genetic disorder could have been involved in this patient's susceptibility to thrombosis [19]. Therefore, we cannot exclude that genetic predisposition has played a role in the pathogenesis of arterial thrombosis in this case.
Conclusion Discussion We believe that, since other coagulation disorders could not be demonstrated and given her medical history, the mal use of desmopressin is a plausible cause of the apparent hypercoagulable state and the extensive abdominal arterial thrombosis in this patient. First, in support of this hypothesis, laboratory results showed an impressive elevation in factor VIII activity, vWF:Ag and vWF:RiCo activity (268%, 740%, 590% respectively). Desmopressin increases vWF and factor VIII levels 3 to 5 times both in normal individuals and haemophilia patients [2]. Several other factors present in our patient, i.e. inflammation, (severe) ischaemia and reperfusioninjury, could also have increased plasma vWF levels [3–5]. However, to the best of our knowledge, these levels have never been reported
To the best of our knowledge, in this patient with extensive abdominal arterial thrombosis, vWF and factor VIII levels were much higher than ever reported as a result of inflammation, ischaemia or reperfusion injury. Therefore, although we have no definite proof for the role of desmopressin, the aforementioned data are very suggestive for (the mal use of) oral desmopressin as a cause of this massive abdominal arterial thrombosis.
Acknowledgments We would like to thank dr. P.M. Huisman from the Department of Radiology.
E.J.M. Schrijver et al. / Clinical Biochemistry 45 (2012) 165–167
References [10] [1] Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A. 1-Deamino-8-D-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands' diseases. Lancet 1977;1:869–72. [2] Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997;90:2515–21. [3] Bernardo A, Ball C, Nolasco L, Moake JF, Dong JF. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 2004;104:100–6. [4] Abu-Zidan FM, Farrant G, Zwi LJ, Simovic MO, Day T, Bonham MJ, et al. Plasma von Willebrand factor and intestinal ischaemia-reperfusion injury in rats. Thromb Res 1999;94:353–8. [5] O'Donnell J, Tuddenham EG, Manning R, Kemball-Cook G, Johnson D, Laffan M. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997;77:825–8. [6] Reiter RA, Varadi K, Turecek PL, Jilma B, Knobl P. Changes in ADAMTS13 (von-Willebrand-factor-cleaving protease) activity after induced release of von Willebrand factor during acute systemic inflammation. Thromb Haemost 2005;93:554–8. [7] [No authors listed]. Desmopressin and arterial thrombosis. Lancet 1989;1:938–9. [8] O'Brien JR, Green PJ, Salmon G, Weir P, Colin-Jones D, Arnold M, et al. Desmopressin and myocardial infarction. Lancet 1989;1:664–5. [9] Rembratt A, Graugaard-Jensen C, Senderovitz T, Norgaard JP, Djurhuus JC. Pharmacokinetics and pharmacodynamics of desmopressin administered orally versus
[11] [12] [13] [14] [15]
[16]
[17] [18] [19]
167
intravenously at daytime versus night-time in healthy men aged 55–70 years. Eur J Clin Pharmacol 2004;60:397–402. Bertholini DM, Butler CS. Severe hyponatraemia secondary to desmopressin therapy in von Willebrand's disease. Anaesth Intensive Care 2000;28:199–201. Kelleher HB, Henderson SO. Severe hyponatremia due to desmopressin. J Emerg Med 2006;30:45–7. Squizzato A, Gerdes VE, Buller HR. Effects of human cytomegalovirus infection on the coagulation system. Thromb Haemost 2005;93:403–10. Uthman IW, Gharavi AE. Viral infections and antiphospholipid antibodies. Semin Arthritis Rheum 2002;31:256–63. Koenigs KP, McPhedran P, Spiro HM. Thrombosis in inflammatory bowel disease. J Clin Gastroenterol 1987;9:627–31. Coller BS, Owen J, Jesty J, Horowitz D, Reitman MJ, Spear J, et al. Deficiency of plasma protein S, protein C, or antithrombin III and arterial thrombosis. Arteriosclerosis 1987;7:456–62. Favaloro EJ, Lippi G. Laboratory reporting of hemostasis assays: the final postanalytical opportunity to reduce errors of clinical diagnosis in hemostasis? Clin Chem Lab Med 2010;48:309–21. Margetic S. Diagnostic algorithm for thrombophilia screening. Clin Chem Lab Med 2010;48(Suppl. 1):S27–39. Munster AM, Sidelmann JJ, Gram J. Thrombophilia screening in the acute phase of deep venous thrombosis. Scand J Clin Lab Invest 2009;69:633–5. Souto JC, Almasy L, Borrell M, Blanco-Vaca F, Mateo J, Soria JM, et al. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic analysis of idiopathic thrombophilia. Am J Hum Genet 2000;67:1452–9.
Contents lists available at SciVerse ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Case Report
An unusual case of abdominal arterial thrombosis in a young woman using desmopressin E.J.M. Schrijver a,⁎, W. Deenik b, H. Chon c, N. Koedam d, A.M.E. Spoelstra-de Man a a
Tergooiziekenhuizen Hilversum, Department of Intensive Care, Van Riebeeckweg 212, 1213 XZ Hilversum, the Netherlands Tergooiziekenhuizen Hilversum, Department of Internal Medicine, Van Riebeeckweg 212, 1213 XZ Hilversum, the Netherlands Tergooiziekenhuizen Hilversum, Department of Clinical Chemistry, Van Riebeeckweg 212, 1213 XZ Hilversum, the Netherlands d Tergooiziekenhuizen Hilversum, Department of Surgery, Van Riebeeckweg 212, 1213 XZ Hilversum, the Netherlands b c
a r t i c l e
i n f o
Article history: Received 2 September 2011 received in revised form 4 November 2011 accepted 17 November 2011 Available online 2 December 2011 Keywords: Desmopressin Arterial thrombosis
a b s t r a c t We report an unusual case of severe abdominal arterial thrombosis in a young woman using oral desmopressin. Only a few cases with cerebrovascular accidents and coronary syndromes have been described so far, which could be attributed to intravenous administration of desmopressin. Because extensive diagnostic and laboratory investigations for (un)common coagulation disorders could not identify an alternative explanation associated with arterial thrombosis, we hypothesise that desmopressin in an oral dose of at least 200 ug once daily must have been sufficient to cause this dramatic vascular complication. Supportive of our hypothesis, we found remarkably high levels of factor VIII activity, Von Willebrand factor (vWF) antigen and vWF ristocetin cofactor activity (268%, 740%, 590% respectively). To the best of the authors' knowledge, this is the first report suggesting a relationship between oral desmopressin use and life-threatening abdominal arterial thrombosis. © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Introduction Desmopressin (1-deamino-8-D-arginine vasopressin, abbreviated DDAVP) is a synthetic vasopressin analogue (V2-receptor agonist). This drug is prescribed for the treatment of diabetes insipidus and nocturnal enuresis, because of its specific antidiuretic effect. Desmopressin stimulates the release of von Willebrand Factor (vWF) from vascular endothelial cells and raises plasma levels of factor VIII, hereby shortening the bleeding time, making it an effective drug to treat patients with coagulation disorders such as haemophilia A and von Willebrand disease (vWD) [1].
Case report A 27-year-old woman presented at the emergency room with a 7-week history of abdominal pain and diarrhoea. She was treated by her general practitioner for a Clostridium difficile-associated diarrhoea with metronidazole 500 mg orally three times daily for 10 days. Her medical history included borderline personality disorder with multiple auto-intoxications requiring hospital admission. Because of nocturnal enuresis, she was prescribed desmopressin 200 ug once daily since approximately 3 months next to aripiprazole, citalopram, alprazolam and topiramate. On physical examination her vital signs were normal. ⁎ Corresponding author. E-mail address: [email protected] (E.J.M. Schrijver).
Abdominal examination revealed decreased bowel sounds with diffuse abdominal pain without muscular defence. Rectal examination was normal. Laboratory results included a sodium level of 132 mmol/L (137–144), a potassium level of 3.3 mmol/L (3.5–5.0), C-reactive protein 180 mg/L (b5.0), leukocyte count of 23.7 × 10 9/L (4.0–11.0) with 10% of band-forms in the differential count, lactate 4.8 mmol/L (b2.0) and a creatinine level of 47 umol/L (50–95). Coagulation tests were not performed in the emergency room. An abdominal CT scan showed an ileus of the small intestine with thickening of the jejunum. Gastroscopy showed severe reflux oesophagitis. She was admitted to hospital for observation. Because of clinical deterioration and an increase in plasma C-reactive protein and lactate, an exploratory laparotomy was performed the day after admission. Unexpectedly, this exploratory laparotomy revealed extensive small bowel ischaemia 30 cm distal to the ligament of Treitz until 50 cm proximal to the ileocoecal valve. Part of the left lobe of the liver appeared necrotic, as well as a part of the spleen. The colon and sigmoid were both well-perfused. The abdomen was temporarily closed to perform a per-operative abdominal contrast-enhanced CT-scan, which showed occlusion of the coeliac trunk, hepatic artery, lineal artery, left gastric artery and superior mesenteric artery (4 cm from its origin) (Fig. 1). A thrombectomy of these arteries was performed and therapeutic doses of unfractionated heparin were infused. Remarkably, thrombosis of the celiac trunk immediately recurred during the procedure, suggestive of a severe coagulation disorder. An aortahepatic bypass was made and the majority of the small bowel was resected, leaving a residual small intestinal length of less than 100 cm.
0009-9120/$ – see front matter © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2011.11.011
166
E.J.M. Schrijver et al. / Clinical Biochemistry 45 (2012) 165–167
Fig. 1. Thrombus in the celiac trunk (CT scan, arterial phase).
A severe coagulation disorder was suspected as the underlying cause of extensive arterial thrombosis in this young woman. A catastrophic antiphospholipid syndrome could not be confirmed: lupus anticoagulant (LAC) antibodies, beta-2 glycoprotein-I (B2GP1) antibodies and anticardiolipin antibodies (ACA) were all negative. Additional testing for coagulation disorders, like factor V Leiden, prothrombin G20210A and Jak-2 V617F gene mutation, showed no abnormalities. Measurements of protein C (normal activity range 75–125%), protein S (normal plasma activity range 70–130%) and antithrombin (AT) III (normal plasma pool activity range 80–120%) in the acute phase of thrombosis all showed decreased activity (42%, 48% and 43% respectively). Homocysteine levels were not measured. Paroxysmal nocturnal haemoglobinuria (PNH) was excluded since flow cytometry of peripheral blood revealed normal CD55/CD59 expression, and positive fluorescent cell labelling of the protein aerolysin (FLAER) rejected the presence of PNH granulocytes. Anti-nuclear antibodies (ANA) and anti-neutrophilic cytoplasmic antibodies (ANCA) were negative. Further results showed remarkable elevations in factor VIII activity, von Willebrand factor antigen (vWF:Ag) and vWF ristocetin cofactor (vWF:RiCo) activity (268%, 740%, 590% respectively). There were no signs of vasculitis, or atherosclerosis on histopathological investigation. Transesophageal echocardiography did not show left atrial thrombus or left ventricular thrombus.
to be as high as observed in our patient. For example, in endotoxininduced systemic inflammation, increased vWF:Ag of up to 259 ± 16% of the baseline value has been detected [6], whereas vWF:Ag was 740% in our case. Second, arterial thrombotic events associated with the use of desmopressin have been reported before. A few cases with cerebrovascular accidents and coronary syndromes have been described which could be attributed to the intravenous administration of desmopressin [7,8]. Noteworthy, our patient used oral desmopressin. However, the pharmacodynamic effects of oral desmopressin (200 ug) have been shown to be similar in magnitude to those after an intravenous dose (2 ug) at night and during the first 6 hours after daytime administration in healthy men aged 55–70 years, despite low bioavailability of orally administered desmopressin (0.08%) [9]. Third, another argument supporting our hypothesis that desmopressin played an important role in the pathophysiology of arterial thrombosis is that our patient was hyponatriemic on admission. Desmopressin binds to V2 receptors in renal collecting ducts, hereby increasing the reabsorption of water, leading to hyponatremia from simple overhydration. Although mild, and in this case other causes may have contributed to this patient's hyponatremia (e.g. diarrhoea in combination with low intake accompanying abdominal pain), numerous reports exist on cases of mild to moderate and even severe desmopressin-induced hyponatremia in healthy adults and individuals with von Willebrand's disease (vWD) [10,11]. Quantified plasma desmopressin concentrations at time of admission could have confirmed our hypothesis. Unfortunately, no direct sample suitable to measure plasma desmopressin levels was collected at that time. Considering other causes of arterial thrombosis, different infectious pathogens have been suggested as responsible agents for thrombotic disorders by the induction of antiphospholipid antibodies, the presence of ACA and/or LAC [12,13]. In this case, the patient was diagnosed and treated for a C. difficile infection by her general practitioner before hospital admission. However, since above-mentioned antibodies were all negative, we reject a possible role for C. difficileinduced pseudomembranous colitis as a trigger for the thrombosis in this patient [14]. Hereditary thrombophilia mostly triggers venous thrombotic events, but there are reports on arterial thrombosis secondary to reduced protein S and protein C activity [15]. Protein C, protein S and ATIII plasma activity were all in the lower range in our patient, most likely due to consumption coagulopathy. Notably, the tests in our patient were performed during the acute phase of thrombosis, which is unreliable [16–18]. In addition, a still unknown genetic disorder could have been involved in this patient's susceptibility to thrombosis [19]. Therefore, we cannot exclude that genetic predisposition has played a role in the pathogenesis of arterial thrombosis in this case.
Conclusion Discussion We believe that, since other coagulation disorders could not be demonstrated and given her medical history, the mal use of desmopressin is a plausible cause of the apparent hypercoagulable state and the extensive abdominal arterial thrombosis in this patient. First, in support of this hypothesis, laboratory results showed an impressive elevation in factor VIII activity, vWF:Ag and vWF:RiCo activity (268%, 740%, 590% respectively). Desmopressin increases vWF and factor VIII levels 3 to 5 times both in normal individuals and haemophilia patients [2]. Several other factors present in our patient, i.e. inflammation, (severe) ischaemia and reperfusioninjury, could also have increased plasma vWF levels [3–5]. However, to the best of our knowledge, these levels have never been reported
To the best of our knowledge, in this patient with extensive abdominal arterial thrombosis, vWF and factor VIII levels were much higher than ever reported as a result of inflammation, ischaemia or reperfusion injury. Therefore, although we have no definite proof for the role of desmopressin, the aforementioned data are very suggestive for (the mal use of) oral desmopressin as a cause of this massive abdominal arterial thrombosis.
Acknowledgments We would like to thank dr. P.M. Huisman from the Department of Radiology.
E.J.M. Schrijver et al. / Clinical Biochemistry 45 (2012) 165–167
References [10] [1] Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A. 1-Deamino-8-D-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands' diseases. Lancet 1977;1:869–72. [2] Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997;90:2515–21. [3] Bernardo A, Ball C, Nolasco L, Moake JF, Dong JF. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 2004;104:100–6. [4] Abu-Zidan FM, Farrant G, Zwi LJ, Simovic MO, Day T, Bonham MJ, et al. Plasma von Willebrand factor and intestinal ischaemia-reperfusion injury in rats. Thromb Res 1999;94:353–8. [5] O'Donnell J, Tuddenham EG, Manning R, Kemball-Cook G, Johnson D, Laffan M. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997;77:825–8. [6] Reiter RA, Varadi K, Turecek PL, Jilma B, Knobl P. Changes in ADAMTS13 (von-Willebrand-factor-cleaving protease) activity after induced release of von Willebrand factor during acute systemic inflammation. Thromb Haemost 2005;93:554–8. [7] [No authors listed]. Desmopressin and arterial thrombosis. Lancet 1989;1:938–9. [8] O'Brien JR, Green PJ, Salmon G, Weir P, Colin-Jones D, Arnold M, et al. Desmopressin and myocardial infarction. Lancet 1989;1:664–5. [9] Rembratt A, Graugaard-Jensen C, Senderovitz T, Norgaard JP, Djurhuus JC. Pharmacokinetics and pharmacodynamics of desmopressin administered orally versus
[11] [12] [13] [14] [15]
[16]
[17] [18] [19]
167
intravenously at daytime versus night-time in healthy men aged 55–70 years. Eur J Clin Pharmacol 2004;60:397–402. Bertholini DM, Butler CS. Severe hyponatraemia secondary to desmopressin therapy in von Willebrand's disease. Anaesth Intensive Care 2000;28:199–201. Kelleher HB, Henderson SO. Severe hyponatremia due to desmopressin. J Emerg Med 2006;30:45–7. Squizzato A, Gerdes VE, Buller HR. Effects of human cytomegalovirus infection on the coagulation system. Thromb Haemost 2005;93:403–10. Uthman IW, Gharavi AE. Viral infections and antiphospholipid antibodies. Semin Arthritis Rheum 2002;31:256–63. Koenigs KP, McPhedran P, Spiro HM. Thrombosis in inflammatory bowel disease. J Clin Gastroenterol 1987;9:627–31. Coller BS, Owen J, Jesty J, Horowitz D, Reitman MJ, Spear J, et al. Deficiency of plasma protein S, protein C, or antithrombin III and arterial thrombosis. Arteriosclerosis 1987;7:456–62. Favaloro EJ, Lippi G. Laboratory reporting of hemostasis assays: the final postanalytical opportunity to reduce errors of clinical diagnosis in hemostasis? Clin Chem Lab Med 2010;48:309–21. Margetic S. Diagnostic algorithm for thrombophilia screening. Clin Chem Lab Med 2010;48(Suppl. 1):S27–39. Munster AM, Sidelmann JJ, Gram J. Thrombophilia screening in the acute phase of deep venous thrombosis. Scand J Clin Lab Invest 2009;69:633–5. Souto JC, Almasy L, Borrell M, Blanco-Vaca F, Mateo J, Soria JM, et al. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic analysis of idiopathic thrombophilia. Am J Hum Genet 2000;67:1452–9.